Therapeutic compounds

ABSTRACT

The invention provides compounds having Formula (I):or a pharmaceutically acceptable salt thereof, as well as pharmaceutical compositions comprising the same, processes for their preparation, and methods of treating and preventing HIV infection by their administration.

FIELD

This application relates to chemical compounds that may inhibit humanimmunodeficiency virus (HIV), to compositions and formulationscontaining such compounds, and to methods of using and making suchcompounds.

BACKGROUND

Positive-single stranded RNA viruses comprising the Retroviridae familyinclude those of the subfamily Orthoretrovirinae and generaAlpharetrovirus, Betaretrovirus, Gamaretrovirus, Deltaretrovirus,Epsilonretrovirus, Lentivirus, and Spumavirus which cause many human andanimal diseases. Among the Lentivirus, HIV-1 infection in humans leadsto depletion of T helper cells and immune dysfunction, producingimmunodeficiency and vulnerability to opportunistic infections. TreatingHIV-1 infections with highly active antiretroviral therapies (HAART) hasproven to be effective at reducing viral load and significantly delayingdisease progression (Hammer, S. M., et al.; JAMA 2008, 300: 555-570).However, these treatments could lead to the emergence of HIV strainsthat are resistant to current therapies (Taiwo, B., InternationalJournal of Infectious Diseases 2009, 13:552-559; Smith, R. J., et al.,Science 2010, 327:697-701). Therefore, there is a pressing need todiscover new antiretroviral agents that are active against emergingdrug-resistant HIV variants.

SUMMARY

Provided herein are compounds and methods for the treatment orprevention of HIV (i.e., human immunodeficiency virus) infection.

In some embodiments, disclosed herein is a compound of Formula (I):

-   wherein-   A is 3-6 membered carbocycle;-   n is 0, 1, or 2;-   m is 0, 1, or 2;-   R¹ is 5-12 membered heteroaryl or 5-12 membered heterocycle, wherein    any 5-12 membered heteroaryl or 5-12 membered heterocycle of R¹ is    unsubstituted or substituted with 1, 2, 3, 4 or 5 Z¹ groups, wherein    the Z¹ groups are the same or different;-   each Z¹ is independently (C₁-C₆)alkyl, (C₃-C₇)carbocycle, halogen,    or —CN, wherein any (C₁-C₆)alkyl or (C₃-C₇)carbocycle of Z¹ is    unsubstituted or substituted with 1, 2, 3, 4 or 5 Z^(1a) groups,    wherein the Z^(1a) groups are the same or different;-   each Z^(1a) is independently halogen, (C₃-C₇)carbocycle, —OH, or    —CN;-   R² is hydrogen, halogen, —OH, or —CN;-   R³ is (C₁-C₆)alkyl or 3-5 membered heterocycle, wherein the    (C₁-C₆)alkyl is unsubstituted or substituted with 1, 2, or 3 halogen    atoms;-   R⁴ is hydrogen, —S(O)₂—(C₁-C₆)alkyl, —S(O)₂—(C₃-C₆)carbocycle, or    5-6 membered heteroaryl, wherein any —S(O)₂—(C₁-C₆) alkyl,    —S(O)₂—(C₃-C₆)carbocycle, or 5-6 membered heteroaryl of R⁴ is    unsubstituted or substituted with 1, 2, or 3 Z² groups, wherein the    Z² groups are the same or different;-   Z² is (C₁-C₆)alkyl or (C₃-C₆)carbocycle, wherein any (C₁-C₆)alkyl or    (C₃-C₆)carbocycle is unsubstituted or substituted with 1, 2, or 3    Z^(2a) groups, wherein the Z^(2a) groups are the same or different;-   Z^(2a) is hydroxyl or halogen;-   R⁵ is hydrogen or halogen; and-   R⁶ is (C₁-C₃)alkyl;-   or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is a compound of Formula (Ia), ora pharmaceutically acceptable salt thereof,

-   wherein:-   n is 0, 1, or 2;-   m is 0 or 1;-   R¹ is 5-9 membered heteroaryl or 5-9 membered heterocycle, wherein    any 5-9 membered heteroaryl or 5-9 membered heterocycle of R¹ is    unsubstituted or substituted with 1, 2, 3, 4 or 5 Z¹ groups, wherein    the Z¹ groups are the same or different;-   each Z¹ is independently (C₁-C₆)alkyl, (C₃-C₇)carbocycle, or    halogen, wherein any (C₁-C₆)alkyl or (C₃-C₇)carbocycle of Z¹ is    unsubstituted or substituted with 1, 2, 3, 4 or 5 Z^(1a) groups,    wherein the Z^(1a) groups are the same or different;-   each Z^(1a) is independently halogen or (C₃-C₇)carbocycle;-   R² is hydrogen or iodide;-   R³ is (C₁-C₂)alkyl or 3-5 membered heterocycle, wherein the    (C₁-C₂)alkyl is unsubstituted or substituted with 2 or 3 halogen    atoms;-   R⁴ is hydrogen, —S(O)₂—(C₁-C₂)alkyl, —S(O)₂-cyclopropyl, or    5-membered heteroaryl, wherein any —S(O)₂—(C₁-C₂)alkyl,    —S(O)₂-cyclopropyl, or 5-membered heteroaryl of R⁴ is unsubstituted    or substituted with 1, 2, or 3 Z² groups, wherein the Z² groups are    the same or different;-   Z² is (C₁-C₃)alkyl or cyclopropyl, wherein any (C₁-C₃)alkyl or    cyclopropyl is unsubstituted or substituted with 1, 2, or 3 Z^(2a)    groups, wherein the Z^(2a) groups are the same or different;-   Z^(2a) is hydroxyl or fluorine;-   R⁵ is hydrogen, chorine, or fluorine; and-   R⁶ is (C₁-C₃)alkyl.

In some embodiments, disclosed herein is a compound of Formula (Ia), ora pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2;

-   n is 0, 1, or 2;-   m is 0 or 1;-   R¹ is 5-9 membered heteroaryl that is unsubstituted or substituted    with 1, 2, 3, 4 or 5 Z¹ groups, wherein the Z¹ groups are the same    or different;-   each Z¹ is independently (C₁-C₆)alkyl, (C₃-C₇)carbocycle, or    halogen, wherein any (C₁-C₆)alkyl or (C₃-C₇)carbocycle of Z¹ is    unsubstituted or substituted with 1, 2, 3, 4 or 5 Z^(1a) groups,    wherein the Z^(1a) groups are the same or different;-   each Z^(1a) is independently halogen or (C₃-C₇)carbocycle;-   R² is hydrogen or iodide;-   R³ is (C₁-C₂)alkyl or 3-5 membered heterocycle, wherein the    (C₁-C₂)alkyl is unsubstituted or substituted with 2 or 3 fluorine    atoms;-   R⁴ is hydrogen, —S(O)₂—(C₁-C₂)alkyl, —S(O)₂-cyclopropyl, or    5-membered heteroaryl, wherein any —S(O)₂—(C₁-C₂)alkyl,    —S(O)₂-cyclopropyl, or 5-membered heteroaryl of R⁴ is unsubstituted    or substituted with 1, 2, or 3 Z² groups, wherein the Z² groups are    the same or different;-   Z² is (C₁-C₃)alkyl or cyclopropyl, wherein any (C₁-C₃)alkyl or    cyclopropyl is unsubstituted or substituted with 1, 2, or 3 Z^(2a)    groups, wherein the Z^(2a) groups are the same or different;-   Z^(2a) is hydroxyl or fluorine;-   R⁵ is hydrogen, chorine, or fluorine; and-   R⁶ is methyl.

In some embodiments, disclosed herein is a compound of Formula (Ia), ora pharmaceutically acceptable salt thereof, wherein:

-   n is 0, 1, or 2;-   m is 0 or 1;-   R¹ is 5-9 membered heteroaryl that is unsubstituted or substituted    with 1, 2, 3, 4 or 5 Z¹ groups, wherein the Z¹ groups are the same    or different;-   each Z¹ is independently (C₁-C₆)alkyl, (C₃-C₇)carbocycle, or    halogen, wherein any (C₁-C₆)alkyl or (C₃-C₇)carbocycle of Z¹ is    unsubstituted or substituted with 1, 2, 3, 4 or 5 Z^(1a) groups,    wherein the Z^(1a) groups are the same or different;-   each Z^(1a) is independently halogen or (C₃-C₇)carbocycle;-   R² is hydrogen;-   R³ is (C₁-C₂)alkyl or 4 membered heterocycle, wherein the    (C₁-C₂)alkyl is unsubstituted or substituted with 2 or 3 fluorine    atoms;-   R⁴ is —S(O)₂—(C₁-C₂)alkyl, —S(O)₂-cyclopropyl, or 5-membered    heteroaryl, wherein any —S(O)₂—(C₁-C₂)alkyl, —S(O)₂-cyclopropyl, or    5-membered heteroaryl of R⁴ is unsubstituted or substituted with 1,    2, or 3 Z² groups, wherein the Z² groups are the same or different;-   Z² is (C₁-C₃)alkyl or cyclopropyl, wherein any (C₁-C₃)alkyl or    cyclopropyl is unsubstituted or substituted with 1, 2, or 3 Z^(2a)    groups, wherein the Z^(2a) groups are the same or different;-   Z²a is hydroxyl or fluorine;-   R⁵ is hydrogen, chorine, or fluorine; and-   R⁶ is methyl.

In some embodiments, disclosed herein is a compound of Formula (Ib):

or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is a compound of Formula (Ic):

or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is a compound of Formula (Id):

or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is a compound of Formula (Ie):

whereineach X¹ and X² are independently N or CH;or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is a compound of Formula (If):

wherein

X is N or CH;

or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is a compound of Formula (Ig):

whereinq is 0, 1, 2, or 3;each X¹, X², and X³ are independently N or CH;or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is a compound of Formula (Ih):

whereinq is 0, 1, 2, or 3;each X² and X³ are independently N or CH;or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is a compound of Formula (Ii):

whereinq is 0, 1, 2, or 3;each X² and X³ are independently N or CH;or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is a compound of Formula (Ij):

whereinq is 0, 1, 2, or 3;each X¹, X², and X³ are independently N or CH;or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is a compound of Formula (Ik):

whereineach X² and X³ are independently N or CH;or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a pharmaceutical compositioncomprising a compound of disclosed herein or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.Another embodiment provides a pharmaceutical composition comprising acompound as disclosed herein, including a compound of any one offormulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij and Ik, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

In some embodiments, provided herein is a pharmaceutical compositioncomprising a compound of formula I (e.g., a compound of any one offormulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij and Ik) or apharmaceutically acceptable salt thereof; and an additional therapeuticagent, wherein the additional therapeutic agent is an HIV proteaseinhibitor, a HIV non-nucleoside or non-nucleotide inhibitor of reversetranscriptase, a HIV nucleoside or nucleotide inhibitor of reversetranscriptase, a HIV integrase inhibitor, a HIV non-catalytic site (orallosteric) integrase inhibitor, an HIV entry inhibitor, an HIVmaturation inhibitor, a latency reversing agent, a compound that targetsthe HIV capsid, an immune-based therapy, a phosphatidylinositol 3-kinase(PI3K) inhibitor, a HIV antibody, a bispecific antibody and/or“antibody-like” therapeutic protein, a HIV p17 matrix protein inhibitor,a IL-13 antagonist, a peptidyl-prolyl cis-trans isomerase A modulator, aprotein disulfide isomerase inhibitor, a complement C5a receptorantagonist, a DNA methyltransferase inhibitor, a HIV vif gene modulator,a Vif dimerization antagonist, a HIV-1 viral infectivity factorinhibitor, a TAT protein inhibitor, a HIV-1 Nef modulator, a Hcktyrosine kinase modulator, a mixed lineage kinase-3 (MLK-3) inhibitor, aHIV-1 splicing inhibitor, a Rev protein inhibitor, an integrinantagonist, a nucleoprotein inhibitor, a splicing factor modulator, aCOMM domain containing protein 1 modulator, a HIV ribonuclease Hinhibitor, a retrocyclin modulator, a CDK-9 inhibitor, a dendriticICAM-3 grabbing nonintegrin 1 inhibitor, a HIV GAG protein inhibitor, aHIV POL protein inhibitor, a Complement Factor H modulator, a ubiquitinligase inhibitor, a deoxycytidine kinase inhibitor, a cyclin dependentkinase inhibitor, a proprotein convertase PC9 stimulator, a ATPdependent RNA helicase DDX3X inhibitor, a reverse transcriptase primingcomplex inhibitor, a G6PD and NADH-oxidase inhibitor, a pharmacokineticenhancer, a HIV gene therapy, a HIV vaccine, and combinations thereof.

In some embodiments, provided herein is a method for treating aRetroviridae viral infection (e.g., an HIV viral infection) in a mammal(e.g., a human), comprising administering a compound of formula I, or apharmaceutically acceptable salt thereof, to the mammal. Anotherembodiment provides a method for treating a Retroviridae viral infection(e.g., an HIV viral infection) in a mammal (e.g., a human), comprisingadministering a compound as detailed herein, including a compound of anyone of formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij and Ik, or apharmaceutically acceptable salt thereof, to the mammal. Anotherembodiment provides a method for treating a HIV infection in a patientin need thereof comprising administering a therapeutically effectiveamount of a compound as detailed herein, or a pharmaceuticallyacceptable salt thereof, to the patient.

In some embodiments, provided herein is a method for inhibiting theproliferation of the HIV virus, treating AIDS or delaying the onset ofAIDS or ARC symptoms in a mammal (e.g., a human), comprisingadministering a compound of formula I, or a pharmaceutically acceptablesalt thereof, to the mammal. Another embodiment provides a method forinhibiting the proliferation of the HIV virus, treating AIDS or delayingthe onset of AIDS or ARC symptoms in a mammal (e.g., a human),comprising administering a compound as detailed herein, including acompound of any one of formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii,Ij and Ik, or a pharmaceutically acceptable salt thereof, to the mammal.

In some embodiments, provided herein is a method for treating an HIVinfection in a mammal (e.g., a human), comprising administering acompound of formula I, or a pharmaceutically acceptable salt thereof, tothe mammal. Another embodiment provides a method for treating an HIVinfection in a mammal (e.g., a human), comprising administering acompound as detailed herein, including a compound of any one of formulasI, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij and Ik, or a pharmaceuticallyacceptable salt thereof, to the mammal.

In some embodiments, provided herein is a method for treating an HIVinfection in a mammal (e.g., a human), comprising administering to themammal in need thereof a therapeutically effective amount of a compoundof formula I, or a pharmaceutically acceptable salt thereof, incombination with a therapeutically effective amount of one or moreadditional therapeutic agents selected from the group consisting of HIVprotease inhibiting compounds, HIV non-nucleoside inhibitors of reversetranscriptase, HIV nucleoside inhibitors of reverse transcriptase, HIVnucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5inhibitors, capsid polymerization inhibitors, and other drugs fortreating HIV, and combinations thereof. Another embodiment provides amethod for treating an HIV infection in a mammal (e.g., a human),comprising administering to the mammal in need thereof a therapeuticallyeffective amount of a compound of any one of formulas I, Ia, Ib, Ic, Id,Ie, If, Ig, Ih, Ii, Ij and Ik, or a pharmaceutically acceptable saltthereof, in combination with a therapeutically effective amount of oneor more additional therapeutic agents selected from the group consistingof HIV protease inhibiting compounds, HIV non-nucleoside inhibitors ofreverse transcriptase, HIV nucleoside inhibitors of reversetranscriptase, HIV nucleotide inhibitors of reverse transcriptase, HIVintegrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and otherdrugs for treating HIV, and combinations thereof. Another embodimentprovides a method for treating an HIV infection in a patient in needthereof comprising administering to the patient a therapeuticallyeffective amount of a compound as described herein, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of an additional therapeutic agent,wherein the additional therapeutic agent is an HIV protease inhibitingcompound, an HIV non-nucleoside inhibitor of reverse transcriptase, anHIV nucleoside inhibitor of reverse transcriptase, an HIV nucleotideinhibitor of reverse transcriptase, an HIV integrase inhibitor, a gp41inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, acapsid polymerization inhibitor, or a non-catalytic site HIV integrasesite inhibitor and combinations thereof.

In some embodiments, provided herein is a method for treating an HIVinfection in a mammal (e.g., a human), comprising administering to themammal in need thereof a therapeutically effective amount of a compoundof formula I, or a pharmaceutically acceptable salt thereof, incombination with a therapeutically effective amount of an additionaltherapeutic agent, wherein the additional therapeutic agent is a HIVprotease inhibitor, a HIV non-nucleoside or non-nucleotide inhibitor ofreverse transcriptase, a HIV nucleoside or nucleotide inhibitor ofreverse transcriptase, a HIV integrase inhibitor, a HIV non-catalyticsite integrase inhibitor, an HIV entry inhibitor, an HIV maturationinhibitor, a latency reversing agent, a compound that targets the HIVcapsid, an immune-based therapy, a phosphatidylinositol 3-kinase (PI3K)inhibitor, a HIV antibody, a bispecific antibody, an antibody-liketherapeutic protein, a HIV p17 matrix protein inhibitor, a IL-13antagonist, a peptidyl-prolyl cis-trans isomerase A modulator, a proteindisulfide isomerase inhibitor, a complement C5a receptor antagonist, aDNA methyltransferase inhibitor, a HIV vif gene modulator, a Vifdimerization antagonist, a HIV-1 viral infectivity factor inhibitor, aTAT protein inhibitor, a HIV-1 Nef modulator, a Hck tyrosine kinasemodulator, a mixed lineage kinase-3 (MLK-3) inhibitor, a HIV-1 splicinginhibitor, a Rev protein inhibitor, an integrin antagonist, anucleoprotein inhibitor, a splicing factor modulator, a COMM domaincontaining protein 1 modulator, a HIV ribonuclease H inhibitor, aretrocyclin modulator, a CDK-9 inhibitor, a dendritic ICAM-3 grabbingnonintegrin 1 inhibitor, a HIV GAG protein inhibitor, a HIV POL proteininhibitor, a Complement Factor H modulator, a ubiquitin ligaseinhibitor, a deoxycytidine kinase inhibitor, a cyclin dependent kinaseinhibitor, a proprotein convertase PC9 stimulator, a ATP dependent RNAhelicase DDX3X inhibitor, a reverse transcriptase priming complexinhibitor, a G6PD and NADH-oxidase inhibitor, a pharmacokineticenhancer, a HIV gene therapy, or a HIV vaccine. Another embodimentprovides a method for treating an HIV infection in a mammal (e.g., ahuman), comprising administering to the mammal in need thereof atherapeutically effective amount of a compound of any one of formulas I,Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij and Ik, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of an additional therapeutic agent, wherein the additionaltherapeutic agent is a HIV protease inhibitor, a HIV non-nucleoside ornon-nucleotide inhibitor of reverse transcriptase, a HIV nucleoside ornucleotide inhibitor of reverse transcriptase, a HIV integraseinhibitor, a HIV non-catalytic site integrase inhibitor, an HIV entryinhibitor, an HIV maturation inhibitor, a latency reversing agent, acompound that targets the HIV capsid, an immune-based therapy, aphosphatidylinositol 3-kinase (PI3K) inhibitor, a HIV antibody, abispecific antibody, an antibody-like therapeutic protein, a HIV p17matrix protein inhibitor, a IL-13 antagonist, a peptidyl-prolylcis-trans isomerase A modulator, a protein disulfide isomeraseinhibitor, a complement C5a receptor antagonist, a DNA methyltransferaseinhibitor, a HIV vif gene modulator, a Vif dimerization antagonist, aHIV-1 viral infectivity factor inhibitor, a TAT protein inhibitor, aHIV-1 Nef modulator, a Hck tyrosine kinase modulator, a mixed lineagekinase-3 (MLK-3) inhibitor, a HIV-1 splicing inhibitor, a Rev proteininhibitor, an integrin antagonist, a nucleoprotein inhibitor, a splicingfactor modulator, a COMM domain containing protein 1 modulator, a HIVribonuclease H inhibitor, a retrocyclin modulator, a CDK-9 inhibitor, adendritic ICAM-3 grabbing nonintegrin 1 inhibitor, a HIV GAG proteininhibitor, a HIV POL protein inhibitor, a Complement Factor H modulator,a ubiquitin ligase inhibitor, a deoxycytidine kinase inhibitor, a cyclindependent kinase inhibitor, a proprotein convertase PC9 stimulator, aATP dependent RNA helicase DDX3X inhibitor, a reverse transcriptasepriming complex inhibitor, a G6PD and NADH-oxidase inhibitor, apharmacokinetic enhancer, a HIV gene therapy, or a HIV vaccine. Anotherembodiment provides a method for treating an HIV infection in a patientin need thereof comprising administering to the patient atherapeutically effective amount of a compound as described herein, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of an additional therapeutic agent,wherein the additional therapeutic agent is a HIV protease inhibitor, aHIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase,a HIV nucleoside or nucleotide inhibitor of reverse transcriptase, a HIVintegrase inhibitor, a HIV non-catalytic site integrase inhibitor, anHIV entry inhibitor, an HIV maturation inhibitor, a latency reversingagent, a compound that targets the HIV capsid, an immune-based therapy,a phosphatidylinositol 3-kinase (PI3K) inhibitor, a HIV antibody, abispecific antibody, an antibody-like therapeutic protein, a HIV p17matrix protein inhibitor, a IL-13 antagonist, a peptidyl-prolylcis-trans isomerase A modulator, a protein disulfide isomeraseinhibitor, a complement C5a receptor antagonist, a DNA methyltransferaseinhibitor, a HIV vif gene modulator, a Vif dimerization antagonist, aHIV-1 viral infectivity factor inhibitor, a TAT protein inhibitor, aHIV-1 Nef modulator, a Hck tyrosine kinase modulator, a mixed lineagekinase-3 (MLK-3) inhibitor, a HIV-1 splicing inhibitor, a Rev proteininhibitor, an integrin antagonist, a nucleoprotein inhibitor, a splicingfactor modulator, a COMM domain containing protein 1 modulator, a HIVribonuclease H inhibitor, a retrocyclin modulator, a CDK-9 inhibitor, adendritic ICAM-3 grabbing nonintegrin 1 inhibitor, a HIV GAG proteininhibitor, a HIV POL protein inhibitor, a Complement Factor H modulator,a ubiquitin ligase inhibitor, a deoxycytidine kinase inhibitor, a cyclindependent kinase inhibitor, a proprotein convertase PC9 stimulator, aATP dependent RNA helicase DDX3X inhibitor, a reverse transcriptasepriming complex inhibitor, a G6PD and NADH-oxidase inhibitor, apharmacokinetic enhancer, a HIV gene therapy, or a HIV vaccine.

In some embodiments, provided herein is a method for treating an HIVinfection in a mammal (e.g., a human), comprising administering to themammal in need thereof a therapeutically effective amount of a compoundof formula I, or a pharmaceutically acceptable salt thereof, incombination with a therapeutically effective amount of one or moreadditional therapeutic agents selected from the group consisting of HIVprotease inhibiting compounds, HIV non-nucleoside inhibitors of reversetranscriptase, HIV nucleoside inhibitors of reverse transcriptase, HIVnucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5inhibitors, capsid polymerization inhibitors, and non-catalytic site HIVintegrase inhibitors, and combinations thereof. Another embodimentprovides a method for treating an HIV infection in a mammal (e.g., ahuman), comprising administering to the mammal in need thereof atherapeutically effective amount of a compound as detailed herein,including a compound of any one of formulas I, Ia, Ib, Ic, Id, Ie, If,Ig, Ih, Ii, Ij and Ik, or a pharmaceutically acceptable salt thereof, incombination with a therapeutically effective amount of one or moreadditional therapeutic agents selected from the group consisting of HIVprotease inhibiting compounds, HIV non-nucleoside inhibitors of reversetranscriptase, HIV nucleoside inhibitors of reverse transcriptase, HIVnucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5inhibitors, capsid polymerization inhibitors, and non-catalytic site HIVintegrase inhibitors, and combinations thereof.

In some embodiments, provided herein is a compound of formula I, or apharmaceutically acceptable salt thereof, for use in medical therapy(e.g., for use in treating a Retroviridae viral infection (e.g., an HIVviral infection) or the proliferation of the HIV virus or AIDS ordelaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human)).Another embodiment provides a compound as detailed herein, including acompound of any one of formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii,Ij and Ik, or a pharmaceutically acceptable salt thereof, for use inmedical therapy (e.g., for use in treating a Retroviridae viralinfection (e.g., an HIV viral infection) or the proliferation of the HIVvirus or AIDS or delaying the onset of AIDS or ARC symptoms in a mammal(e.g., a human)).

In some embodiments, provided herein is a compound of formula I, or apharmaceutically acceptable salt thereof for use in the manufacture of amedicament for treating a Retroviridae viral infection (e.g., an HIVviral infection) or the proliferation of the HIV virus or AIDS ordelaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human).Another embodiment provides a compound as detailed herein, including acompound of any one of formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii,Ij and Ik, or a pharmaceutically acceptable salt thereof, for use in themanufacture of a medicament for treating a Retroviridae viral infection(e.g., an HIV viral infection) or the proliferation of the HIV virus orAIDS or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., ahuman).

In some embodiments, provided herein is a compound of formula I, or apharmaceutically acceptable salt thereof, for use in the prophylactic(e.g., prevention) or therapeutic treatment of the proliferation of aRetroviridae virus, an HIV virus or AIDS or for use in the therapeutictreatment of delaying the onset of AIDS or ARC symptoms. Anotherembodiment provides a compound as detailed herein, including a compoundof any one of formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij and Ik,or a pharmaceutically acceptable salt thereof, for use in theprophylactic (e.g., prevention) or therapeutic treatment of theproliferation of a Retroviridae virus, an HIV virus or AIDS or for usein the therapeutic treatment of delaying the onset of AIDS or ARCsymptoms.

In some embodiments, provided herein is a compound of formula I, or apharmaceutically acceptable salt thereof, for use in the prophylactic(e.g., prevention) or therapeutic treatment of a Retroviridae virusinfection (e.g., an HIV virus infection). Another embodiment provides acompound as detailed herein, including a compound of any one of formulasI, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij and Ik, or a pharmaceuticallyacceptable salt thereof, for use in the prophylactic (e.g., prevention)or therapeutic treatment of a Retroviridae virus infection (e.g., an HIVvirus infection).

In some embodiments, provided herein is a compound of formula I, or apharmaceutically acceptable salt thereof, for use in the prevention of aRetroviridae virus infection (e.g., an HIV virus infection). Anotherembodiment provides a compound as detailed herein, including a compoundof any one of formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij and Ik,or a pharmaceutically acceptable salt thereof, for use in the preventionof a Retroviridae virus infection (e.g., an HIV virus infection).

In some embodiments, provided herein is the use of a compound of formulaI, or a pharmaceutically acceptable salt thereof, for the manufacture ofa medicament for a Retroviridae virus infection (e.g., an HIV virusinfection) in a mammal (e.g., a human). Another embodiment provides acompound as detailed herein, including a compound of any one of formulasI, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij and Ik, or a pharmaceuticallyacceptable salt thereof, for the manufacture of a medicament for aRetroviridae virus infection (e.g., an HIV virus infection) in a mammal(e.g., a human).

In some embodiments, provided herein are processes and intermediatesthat are useful for preparing compounds of formula I or salts thereof.Another embodiment provides processes and intermediates disclosed hereinthat are useful for preparing compounds of any one of formulas I, Ia,Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij and Ik, or salts thereof.

Other embodiments, objects, features and advantages will be set forth inthe detailed description of the embodiments that follows, and in partwill be apparent from the description, or may be learned by practice, ofthe claimed invention. These objects and advantages will be realized andattained by the processes and compositions particularly pointed out inthe written description and claims hereof. The foregoing Summary hasbeen made with the understanding that it is to be considered as a briefand general synopsis of some of the embodiments disclosed herein, isprovided solely for the benefit and convenience of the reader, and isnot intended to limit in any manner the scope, or range of equivalents,to which the appended claims are lawfully entitled.

DETAILED DESCRIPTION

The description below is made with the understanding that the presentdisclosure is to be considered as an exemplification of the claimedsubject matter, and is not intended to limit the appended claims to thespecific embodiments illustrated. The headings used throughout thisdisclosure are provided for convenience only and are not to be construedto limit the claims in any way. Embodiments illustrated under anyheading may be combined with embodiments illustrated under any otherheading.

I. Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art. A dash at the front or end of a chemical group is a matter ofconvenience; chemical groups may be depicted with or without one or moredashes without losing their ordinary meaning. A wavy line drawn througha line in a structure indicates a point of attachment of a group, e.g.,

A dashed line indicates an optional bond. A dash at the front or end ofa chemical group is a matter of convenience; chemical groups may bedepicted with or without one or more dashes without losing theirordinary meaning. When used, a dash indicates the point of attachment,e.g. —S(O)(R^(a))═NR^(b) indicates the following structure with point ofattachment at the S:

A prefix such as “C_(u-v)”, “(C_(u-v))”, or (C_(u)-C_(v)) indicate thatthe following group has from u to v carbon atoms. For example,“C₁₋₆alkyl”, “(C₁₋₆)alkyl”, and “(C₁₋₆)alkyl” indicate that the alkylgroup has from 1 to 6 carbon atoms.

Unless stated otherwise, the following terms and phrases as used hereinare intended to have the following meanings:

When trade names are used herein, applicants intend to independentlyinclude the tradename product and the active pharmaceuticalingredient(s) of the tradename product.

“Alkyl” is a straight or branched saturated hydrocarbon. For example, analkyl group can have 1 to 8 carbon atoms (i.e., (C₁-C₈)alkyl) or 1 to 6carbon atoms (i.e., (C₁-C₆ alkyl) or 1 to 4 carbon atoms (i.e.,(C₁-C₄)alkyl). Examples of suitable alkyl groups include, but are notlimited to, methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl n-propyl,—CH₂CH₂CH₃), 2-propyl —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl,—CH₂CH₂CH₂CH₃), 2-methyl-1-propyl i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu,s-butyl, —CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃),1-pentyl (n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃),3-pentyl (—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃),3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂),2-methyl-1-butyl (—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃),2-hexyl (—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, and octyl (—(CH₂)₇CH₃).

“Alkenyl” is a straight or branched hydrocarbon with at least onecarbon-carbon, sp² double bond. For example, an alkenyl group can have 2to 8 carbon atoms (i.e., C₂-C₈ alkenyl), or 2 to 6 carbon atoms (i.e.,C₂-C₆ alkenyl). Examples of suitable alkenyl groups include, but are notlimited to, ethylene or vinyl (—CH═CH₂), allyl (—CH₂CH═CH₂) and5-hexenyl (—CH₂CH₂CH₂CH₂CH═CH₂).

“Alkynyl” is a straight or branched hydrocarbon with at least onecarbon-carbon, sp triple bond. For example, an alkynyl group can have 2to 8 carbon atoms (i.e., C₂-C₈ alkyne) or 2 to 6 carbon atoms (i.e.,C₂-C₆ alkynyl). Examples of suitable alkynyl groups include, but are notlimited to, acetylenic (—C≡CH), propargyl (—CH₂C≡CH), and the like.

The term “halo” or “halogen” as used herein refers to fluoro, chloro,bromo and iodo.

The term “haloalkyl” as used herein refers to an alkyl as definedherein, wherein one or more hydrogen atoms of the alkyl are eachindependently replaced by a halo substituent. For example,(C₁-C₆)haloalkyl is a (C₁-C₆)alkyl wherein one or more of the hydrogenatoms of the (C₁-C₆)alkyl have been replaced by a halo substituent.Examples of haloalkyls include but are not limited to fluoromethyl,fluorochloromethyl, difluoromethyl, difluorochloromethyl,trifluoromethyl, 1,1,1, trifluoroethyl and pentafluoroethyl.

The term “heteroalkyl” as used herein refers to an alkyl as definedherein, wherein one or more of the carbon atoms of the alkyl arereplaced by an O, S, or NR, (or if the carbon atom being replaced is aterminal carbon with an OH, SH or N(R)₂) wherein each R is independentlyH or (C₁-C₆)alkyl. For example, (C₁-C₈)heteroalkyl includes aheteroalkyl of one to eight carbons and one or more heteroatoms (e.g.,O, S, NR, OH, SH or N(R)₂). Thus, for example, a C₁ heteroalkylencompasses, e.g., —CH₂—NH₂. Examples of heteroalkyls include but arenot limited to methoxymethyl, ethoxymethyl, methoxy, 2-hydroxyethyl andN,N′-dimethylpropylamine.

The term “aryl” as used herein refers to a single all carbon aromaticring or a multiple condensed all carbon ring system wherein at least oneof the rings is aromatic. For example, in certain embodiments, an arylgroup has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbonatoms. Aryl includes a phenyl radical. Aryl also includes multiplecondensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings)having about 9 to 20 carbon atoms in which at least one ring is aromaticand wherein the other rings may be aromatic or not aromatic (i.e.,carbocycle). Such multiple condensed ring systems are optionallysubstituted with one or more (e.g., 1, 2 or 3) oxo groups on anycarbocycle portion of the multiple condensed ring system. The rings ofthe multiple condensed ring system can be connected to each other viafused, spiro and bridged bonds when allowed by valency requirements. Itis to be understood that the point of attachment of a multiple condensedring system, as defined above, can be at any position of the ring systemincluding an aromatic or a carbocycle portion of the ring. It is also tobe understood that when reference is made to a certain atom-rangemembered aryl (e.g., 6-12 membered aryl), the atom range is for thetotal ring atoms of the aryl. For example, a 6-membered aryl wouldinclude phenyl and a 10-membered aryl would include naphthyl and 1, 2,3, 4-tetrahydronaphthyl. Non-limiting examples of aryl groups include,but are not limited to, phenyl, indenyl, naphthyl, 1, 2, 3,4-tetrahydronaphthyl, anthracenyl, and the like.

The term “heteroaryl” as used herein refers to a single aromatic ringthat has at least one atom other than carbon in the ring, wherein theatom is selected from the group consisting of oxygen, nitrogen andsulfur; “heteroaryl” also includes multiple condensed ring systems thathave at least one such aromatic ring, which multiple condensed ringsystems are further described below. Thus, “heteroaryl” includes singlearomatic rings of from about 1 to 6 carbon atoms and about 1-4heteroatoms selected from the group consisting of oxygen, nitrogen andsulfur. The sulfur and nitrogen atoms may also be present in an oxidizedform provided the ring is aromatic. Exemplary heteroaryl ring systemsinclude but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl.“Heteroaryl” also includes multiple condensed ring systems (e.g., ringsystems comprising 2, 3 or 4 rings) wherein a heteroaryl group, asdefined above, is condensed with one or more rings selected fromheteroaryls (to form for example 1,8-naphthyridinyl), heterocycles, (toform for example 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycles (toform for example 5,6,7,8-tetrahydroquinolyl) and aryls (to form forexample indazolyl) to form the multiple condensed ring system. Thus, aheteroaryl (a single aromatic ring or multiple condensed ring system)has about 1-20 carbon atoms and about 1-6 heteroatoms within theheteroaryl ring. Such multiple condensed ring systems may be optionallysubstituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on thecarbocycle or heterocycle portions of the condensed ring. The rings ofthe multiple condensed ring system can be connected to each other viafused, spiro and bridged bonds when allowed by valency requirements. Itis to be understood that the individual rings of the multiple condensedring system may be connected in any order relative to one another. It isalso to be understood that the point of attachment of a multiplecondensed ring system (as defined above for a heteroaryl) can be at anyposition of the multiple condensed ring system including a heteroaryl,heterocycle, aryl or carbocycle portion of the multiple condensed ringsystem. It is also to be understood that the point of attachment for aheteroaryl or heteroaryl multiple condensed ring system can be at anysuitable atom of the heteroaryl or heteroaryl multiple condensed ringsystem including a carbon atom and a heteroatom (e.g., a nitrogen). Italso to be understood that when a reference is made to a certainatom-range membered heteroaryl (e.g., a 5-14 membered heteroaryl), theatom range is for the total ring atoms of the heteroaryl and includescarbon atoms and heteroatoms. For example, a 5-membered heteroaryl wouldinclude a thiazolyl and a 10-membered heteroaryl would include aquinolinyl. Exemplary heteroaryls include but are not limited topyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl,thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl,oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl,benzoxazolyl, indazolyl, quinoxalyl, quinazolyl,5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl,thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one,triazolyl, 4,5,6,7-tetrahydro-1H-indazole and3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole.

The term “C-linked-heteroaryl” (carbon-linked heteroaryl) as used hereinrefers to a heteroaryl that is linked at a carbon atom of the heteroarylto the remainder of the compound of formula I (e.g., aC-linked-heteroaryl of Z² bonded to the A ring of formula I through acarbon atom of the C-linked-heteroaryl).

The term “heterocyclyl” or “heterocycle” as used herein refers to asingle saturated or partially unsaturated ring that has at least oneatom other than carbon in the ring, wherein the atom is selected fromthe group consisting of oxygen, nitrogen and sulfur; the term alsoincludes multiple condensed ring systems that have at least one suchsaturated or partially unsaturated ring, which multiple condensed ringsystems are further described below. Thus, the term includes singlesaturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-memberedrings) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatomsselected from the group consisting of oxygen, nitrogen and sulfur in thering. The ring may be substituted with one or more (e.g., 1, 2 or 3) oxogroups and the sulfur and nitrogen atoms may also be present in theiroxidized forms. Exemplary heterocycles include but are not limited toazetidinyl, tetrahydrofuranyl and piperidinyl. The term “heterocycle”also includes multiple condensed ring systems (e.g., ring systemscomprising 2, 3 or 4 rings) wherein a single heterocycle ring (asdefined above) can be condensed with one or more groups selected fromheterocycles (to form for example a 1,8-decahydronapthyridinyl),carbocycles (to form for example a decahydroquinolyl) and aryls to formthe multiple condensed ring system. Thus, a heterocycle (a singlesaturated or single partially unsaturated ring or multiple condensedring system) has about 2-20 carbon atoms and 1-6 heteroatoms within theheterocycle ring. Such multiple condensed ring systems may be optionallysubstituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on thecarbocycle or heterocycle portions of the multiple condensed ring. Therings of the multiple condensed ring system can be connected to eachother via fused, spiro and bridged bonds when allowed by valencyrequirements. It is to be understood that the individual rings of themultiple condensed ring system may be connected in any order relative toone another. It is also to be understood that the point of attachment ofa multiple condensed ring system (as defined above for a heterocycle)can be at any position of the multiple condensed ring system including aheterocycle, aryl and carbocycle portion of the ring. It is also to beunderstood that the point of attachment for a heterocycle or heterocyclemultiple condensed ring system can be at any suitable atom of theheterocycle or heterocycle multiple condensed ring system including acarbon atom and a heteroatom (e.g., a nitrogen). It is also to beunderstood that when reference is made to a certain atom-range memberedheterocycle (e.g., a 3-14 membered heterocycle), the atom range is forthe total ring atoms of the heterocycle and includes carbon atoms andheteroatoms. For example, a 3-membered heterocycle would include anaziridinyl and a 10-membered heterocycle would include a1,2,3,4-tetrahydroquinolyl. Exemplary heterocycles include, but are notlimited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl,tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl,dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl,2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl,spiro[cyclopropane-1,1′-isoindolinyl]-3′-one, isoindolinyl-1-one,2-oxa-6-azaspiro[3.3]heptanyl, imidazolidin-2-one and pyrrolidin-2-one.

The term “C-linked-heterocycle” (carbon-linked heterocycle) as usedherein refers to a “heterocycle that is linked at a carbon atom of theheterocycle to the remainder of the compound of formula I.

The term “carbocycle” refers to a cyclic alkyl and alkenyl groups. Acarbocycle group can have one or more cyclic rings and includes fusedand bridged groups that are fully saturated or partially unsaturated.Examples include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, adamantyl, methylcycloproyl(cyclopropylmethyl), ethylcyclopropyl, cyclohexenyl and the like.

The term “fused” refers to a ring which is bound to an adjacent ring.

“Bridged” refers to a ring fusion wherein non-adjacent atoms on a ringare joined by a divalent substituent, such as an alkylenyl orheteroalkylenyl group or a single heteroatom. Quinuclidinyl andadmantanyl are examples of bridged ring systems.

“Spiro” refers to a ring substituent which is joined by two bonds at thesame carbon atom. Examples of spiro groups include1,1-diethylcyclopentane, dimethyl-dioxolane, and4-benzyl-4-methylpiperidine, wherein the cyclopentane and piperidine,respectively, are the spiro substituents.

The phrase “meta (3) position with respect to the point of attachment ofthe A ring”, refers to the position on the ring where the substituent(e.g. —CN) is adjoined and is shown below with an arrow, wherein zrepresents a carbon atom or nitrogen:

Similarly, para (4) position substitution refers to attachment of asubstituent at the position indicated below, with respect to the pointof attachment (e.g. of the B ring):

Similarly, ortho or 2-position refers to attachment of a substituent atthe position indicated below, with respect to the point of attachment:

The term “halophenyl” as used herein refers to phenyl, wherein one ormore (e.g., 1, 2, 3, 4 or 5) hydrogen atoms of the phenyl are eachreplaced independently by a halo substituent. Examples of halophenylinclude but are not limited to fluorophenyl, 2,3-dichlorophenyl,3-bromo-4-fluorophenyl and pentafluorophenyl.

The term “haloheteroaryl” as used herein refers to a heteroaryl, whereinone or more (e.g., 1, 2, 3, 4 or 5) hydrogen atoms of the heteroaryl areeach replaced independently by a halo substituent. Examples ofhaloheteroaryl include but are not limited to 2-fluorofuryl,2,3-dichloropyridinyl and 8-chloro-3-fluoroquinolinyl.

The term “haloheterocycle” as used herein refers to a heterocycle,wherein one or more (e.g., 1, 2, 3, 4 or 5) hydrogen atoms of theheterocycle are each replaced independently by a halo substituent.Examples of haloheteroaryl include but are not limited to2-fluoropiperidinyl, 2-chloro-3-fluoropiperazinyl and3-bromopyrrolidinyl.

One skilled in the art will recognize that substituents and othermoieties of the compounds of formula I should be selected in order toprovide a compound which is sufficiently stable to provide apharmaceutically useful compound which can be formulated into anacceptably stable pharmaceutical composition. Compounds of formula Iwhich have such stability are contemplated as falling within the scopeof the present invention. Similarly, one skilled in the art willrecognize that substituents and other moieties of the compounds detailedherein, including a compound of any one of formulas I, Ia, Ib, Ic, Id,Ie, If, Ig, Ih, Ii, Ij and Ik, or a pharmaceutically acceptable saltthereof, should be selected in order to provide a compound which issufficiently stable to provide a pharmaceutically useful compound whichcan be formulated into an acceptably stable pharmaceutical composition.Compounds as detailed herein which have such stability are contemplatedas falling within the scope of the present invention.

The modifier “about” used in connection with a quantity is inclusive ofthe stated value and has the meaning dictated by the context (e.g.,includes the degree of error associated with measurement of theparticular quantity). The word “about” may also be representedsymbolically by “˜” in the context of a chemical measurement (e.g., ˜50mg or pH˜7).

As used herein, “treatment” or “treating” is an approach for obtainingbeneficial or desired results. For purposes of the present disclosure,beneficial or desired results include, but are not limited to,alleviation of a symptom and/or diminishment of the extent of a symptomand/or preventing a worsening of a symptom associated with a disease orcondition. In some embodiments, “treatment” or “treating” includes oneor more of the following: a) inhibiting the disease or condition (e.g.,decreasing one or more symptoms resulting from the disease or condition,and/or diminishing the extent of the disease or condition); b) slowingor arresting the development of one or more symptoms associated with thedisease or condition (e.g., stabilizing the disease or condition,delaying the worsening or progression of the disease or condition);and/or c) relieving the disease or condition, e.g., causing theregression of clinical symptoms, ameliorating the disease state,delaying the progression of the disease, increasing the quality of life,and/or prolonging survival.

As used herein, “delaying” development of a disease or condition meansto defer, hinder, slow, retard, stabilize and/or postpone development ofthe disease or condition. This delay can be of varying lengths of time,depending on the history of the disease and/or subject being treated. Asis evident to one skilled in the art, a sufficient or significant delaycan, in effect, encompass prevention, in that the subject does notdevelop the disease or condition. For example, a method that “delays”development of AIDS is a method that reduces the probability of diseasedevelopment in a given time frame and/or reduces extent of the diseasein a given time frame, when compared to not using the method. Suchcomparisons may be based on clinical studies, using a statisticallysignificant number of subjects. For example, the development of AIDS canbe detected using known methods, such as confirming a subject's HIV⁺status and assessing the subject's T-cell count or other indication ofAIDS development, such as extreme fatigue, weight loss, persistentdiarrhea, high fever, swollen lymph nodes in the neck, armpits or groin,or presence of an opportunistic condition that is known to be associatedwith AIDS (e.g., a condition that is generally not present in subjectswith functioning immune systems but does occur in AIDS patients).Development may also refer to disease progression that may be initiallyundetectable and includes occurrence, recurrence and onset.

As used herein, “prevention” or “preventing” refers to a regimen thatprotects against the onset of the disease or disorder such that theclinical symptoms of the disease do not develop. Thus, “prevention”relates to administration of a therapy (e.g., administration of atherapeutic substance) to a subject before signs of the disease aredetectable in the subject (e.g., administration of a therapeuticsubstance to a subject in the absence of detectable infectious agent(e.g., virus) in the subject). The subject may be an individual at riskof developing the disease or disorder, such as an individual who has oneor more risk factors known to be associated with development or onset ofthe disease or disorder. Thus, the term “preventing HIV infection”refers to administering to a subject who does not have a detectable HIVinfection an anti-HIV therapeutic substance. It is understood that thesubject for anti-HIV preventative therapy may be an individual at riskof contracting the HIV virus. Further, it is understood that preventionmay not result in complete protection against onset of the disease ordisorder. In some instances, prevention includes reducing the risk ofdeveloping the disease or disorder. The reduction of the risk may notresult in complete elimination of the risk of developing the disease ordisorder.

As used herein, an “at risk” individual is an individual who is at riskof developing a condition to be treated. An individual “at risk” may ormay not have detectable disease or condition, and may or may not havedisplayed detectable disease prior to the treatment of methods describedherein. “At risk” denotes that an individual has one or more so-calledrisk factors, which are measurable parameters that correlate withdevelopment of a disease or condition and are known in the art. Anindividual having one or more of these risk factors has a higherprobability of developing the disease or condition than an individualwithout these risk factor(s). For example, individuals at risk for AIDSare those having HIV.

As used herein, the term “therapeutically effective amount” or“effective amount” refers to an amount that is effective to elicit thedesired biological or medical response, including the amount of acompound that, when administered to a subject for treating a disease, issufficient to effect such treatment for the disease or to an amount thatis effective to protect against the contracting or onset of a disease.The effective amount will vary depending on the compound, the disease,and its severity and the age, weight, etc., of the subject to betreated. The effective amount can include a range of amounts. As isunderstood in the art, an effective amount may be in one or more doses,i.e., a single dose or multiple doses may be required to achieve thedesired treatment outcome. An effective amount may be considered in thecontext of administering one or more therapeutic agents, and a singleagent may be considered to be given in an effective amount if, inconjunction with one or more other agents, a desirable or beneficialresult may be or is achieved. Suitable doses of any co-administeredcompounds may optionally be lowered due to the combined action (e.g.,additive or synergistic effects) of the compounds.

Stereoisomers

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., NewYork.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the minor image partner, while the term“achiral” refers to molecules which are superimposable on their minorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers or axesof chirality and whose molecules are not mirror images of one another.Diastereomers typically have different physical properties, e.g.,melting points, boiling points, spectral properties, and reactivities.Mixtures of diastereomers may separate under high resolution analyticalprocedures such as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another. A mixture ofenantiomers at a ratio other than 1:1 is a “scalemic” mixture.

The compounds disclosed herein may have chiral centers, e.g., chiralcarbon atoms. Such compounds thus include racemic mixtures of allstereoisomers, including enantiomers, diastereomers, and atropisomers.In addition, the compounds disclosed herein include enriched or resolvedoptical isomers at any or all asymmetric, chiral atoms. Similarly,compositions disclosed herein also include racemic mixtures of allstereoisomers, including enantiomers, diastereomers, and atropisomers ofcompounds disclosed herein. In addition, the compounds and compositionsdisclosed herein include enriched or resolved optical isomers at any orall asymmetric, chiral atoms. In other words, the chiral centersapparent from the depictions are provided as the chiral isomers orracemic mixtures. Both racemic and diastereomeric mixtures, as well asthe individual optical isomers isolated or synthesized, substantiallyfree of their enantiomeric or diastereomeric partners, are all withinthe scope of the invention. The racemic mixtures can be separated intotheir individual, substantially optically pure isomers throughwell-known techniques such as, for example, the separation ofdiastereomeric salts formed with optically active adjuncts, e.g., acidsor bases followed by conversion back to the optically active substances.The desired optical isomer can also be synthesized by means ofstereospecific reactions, beginning with the appropriate stereoisomer ofthe desired starting material.

The invention includes any or all of the stereochemical forms, includingany enantiomeric or diastereomeric forms and geometric isomers of thecompounds described, or mixtures thereof. Unless stereochemistry isexplicitly indicated in a chemical structure or name, the structure orname is intended to embrace all possible stereoisomers, includinggeometric isomers, of a compound depicted. Compositions comprising acompound of the invention are also intended, such as a composition ofsubstantially pure compound, including a specific stereochemical form,including a specific geometric isomer, thereof. Compositions comprisinga mixture of compounds of the invention in any ratio are also embracedby the invention, including mixtures of two or more stereochemical formsof a compound of the invention in any ratio, such that racemic,non-racemic, enantio-enriched and scalemic mixtures of a compound areembraced, or mixtures thereof.

It is to be understood that for compounds disclosed herein when a bondis drawn in a non-stereochemical manner (e.g., flat) the atom to whichthe bond is attached includes all stereochemical possibilities. It isalso to be understood that when a bond is drawn in a stereochemicalmanner (e.g., bold, bold-wedge, dashed or dashed-wedge) the atom towhich the stereochemical bond is attached has the stereochemistry asshown unless otherwise noted. Accordingly, in some embodiments, acompound disclosed herein is greater than 50% a single enantiomer. Insome embodiments, a compound disclosed herein is at least 80% a singleenantiomer. In some embodiments, a compound disclosed herein is at least90% a single enantiomer. In some embodiments, a compound disclosedherein is at least 98% a single enantiomer. In some embodiments, acompound disclosed herein is at least 99% a single enantiomer. In someembodiments, a compound disclosed herein is greater than 50% a singlediastereomer. In some embodiments, a compound disclosed herein is atleast 80% a single diastereomer. In some embodiments, a compounddisclosed herein is at least 90% a single diastereomer. In someembodiments, a compound disclosed herein is at least 98% a singlediastereomer. In some embodiments, a compound disclosed herein is atleast 99% a single diastereomer.

Accordingly, in some embodiments, a composition disclosed herein isgreater than 50% a single enantiomer. In some embodiments, a compositiondisclosed herein is at least 80% a single enantiomer. In someembodiments, a composition disclosed herein is at least 90% a singleenantiomer. In some embodiments, a composition disclosed herein is atleast 98% a single enantiomer. In some embodiments, a compositiondisclosed herein is at least 99% a single enantiomer. In someembodiments, a composition disclosed herein is greater than 50% a singlediastereomer. In some embodiments, a composition disclosed herein is atleast 80% a single diastereomer. In some embodiments, a compositiondisclosed herein is at least 90% a single diastereomer. In someembodiments, a composition disclosed herein is at least 98% a singlediastereomer. In some embodiments, a composition disclosed herein is atleast 99% a single diastereomer.

In some embodiments, the compounds disclosed herein displayatropisomerism resulting from steric hindrance affecting the axialrotation rate around a single bond. In certain circumstances, theresultant conformational isomers are observed as distinct entities bycharacterization techniques such as NMR and HPLC. In certainembodiments, the compounds disclosed herein exist as a mixture ofatropisomers. The synthetic examples provided herein note where suchmixtures of atropisomers have been observed. However, the detection ofatropisomers is dependent on factors such as temperature, solvent,conditions of purification, and timescale of spectroscopic technique.Characterization data presented herein may not represent the equilibriumstate depending on the conditions of purification, isolation, handling,solvents used, and temperature.

Tautomers

The compounds disclosed herein can also exist as tautomeric isomers incertain cases. Although only one delocalized resonance structure may bedepicted, all such forms are contemplated within the scope of theinvention. For example, ene-amine tautomers can exist for purine,pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and alltheir possible tautomeric forms are within the scope of the invention.Another non-limiting example includes keto-enol tautomers ofheteroaryls. Such tautomers are exemplified by T1/T1′, T2/T2′ andT3/T3′. All such tautomeric forms are also within the scope of theinvention.

Protecting Groups

“Protecting group” refers to a moiety of a compound that masks or altersthe properties of a functional group or the properties of the compoundas a whole. Chemical protecting groups and strategies forprotection/de-protection are well known in the art. See e.g., ProtectiveGroups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons,Inc., New York, 1991. Protecting groups are often utilized to mask thereactivity of certain functional groups, to assist in the efficiency ofdesired chemical reactions, e.g., making and breaking chemical bonds inan ordered and planned fashion. Protection of functional groups of acompound alters other physical properties besides the reactivity of theprotected functional group, such as the polarity, lipophilicity(hydrophobicity), and other properties which can be measured by commonanalytical tools. Chemically protected intermediates may themselves bebiologically active or inactive.

Salts and Hydrates

“Pharmaceutically acceptable salt” refers to a salt of a compound thatis pharmaceutically acceptable and that possesses (or can be convertedto a form that possesses) the desired pharmacological activity of theparent compound. Pharmaceutically acceptable salts are generallyregarded as safe and suitable for use without undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio. Examples of “pharmaceutically acceptablesalts” of the compounds disclosed herein include salts derived from anappropriate base, such as an alkali metal (for example, sodium), analkaline earth metal (for example, magnesium), ammonium and NX₄ ⁺(wherein X is C₁-C₄ alkyl). Pharmaceutically acceptable salts of anitrogen atom or an amino group include for example salts of organiccarboxylic acids such as acetic, benzoic, camphorsulfonic, citric,glucoheptonic, gluconic, lactic, fumaric, tartaric, maleic, malonic,malic, mandelic, isethionic, lactobionic, succinic,2-napththalenesulfonic, oleic, palmitic, propionic, stearic, andtrimethylacetic acids; organic sulfonic acids, such as methanesulfonic,ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; andinorganic acids, such as hydrochloric, hydrobromic, sulfuric, nitric,phosphoric and sulfamic acids. Pharmaceutically acceptable salts of acompound of a hydroxy group include the anion of said compound incombination with a suitable cation such as Na⁺ and NX₄ ⁺ (wherein X isindependently selected from H or a C₁-C₄ alkyl group). Pharmaceuticallyacceptable salts also include salts formed when an acidic proton presentin the parent compound is replaced by either a metal ion, e.g., analkali metal ion, an alkaline earth ion, or an aluminum ion; orcoordinates with an organic base such as diethanolamine,triethanolamine, N-methylglucamine and the like. Also included in thisdefinition are ammonium and substituted or quaternized ammonium salts.Representative non-limiting lists of pharmaceutically acceptable saltscan be found in S. M. Berge et al., J. Pharma Sci., 66(1), 1-19 (1977),and Remington: The Science and Practice of Pharmacy, R. Hendrickson,ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, Pa.,(2005), at p. 732, Table 38-5, both of which are hereby incorporated byreference herein.

For therapeutic use, salts of active ingredients of the compoundsdisclosed herein will typically be pharmaceutically acceptable, i.e.,they will be salts derived from a physiologically acceptable acid orbase. However, salts of acids or bases which are not pharmaceuticallyacceptable may also find use, for example, in the preparation orpurification of a compound of formula I or another compound disclosedherein. All salts, whether or not derived from a physiologicallyacceptable acid or base, are within the scope of the present invention.

Metal salts typically are prepared by reacting the metal hydroxide witha compound disclosed herein. Examples of metal salts which are preparedin this way are salts containing Li⁺, Na⁺, and K⁺. A less soluble metalsalt can be precipitated from the solution of a more soluble salt byaddition of the suitable metal compound.

In addition, salts may be formed from acid addition of certain organicand inorganic acids, e.g., HCl, HBr, H₂SO₄, H₃PO₄ or organic sulfonicacids, to basic centers, such as amines. Finally, it is to be understoodthat the compositions herein comprise compounds disclosed herein intheir un-ionized, as well as zwitterionic form, and combinations withstoichiometric amounts of water as in hydrates.

Often crystallizations produce a solvate of the compound of theinvention. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the invention withone or more molecules of solvent. The solvent may be water, in whichcase the solvate may be a hydrate. Alternatively, the solvent may be anorganic solvent. Thus, the compounds of the present invention may existas a hydrate, including a monohydrate, dihydrate, hemihydrate,sesquihydrate, trihydrate, tetrahydrate and the like, as well as thecorresponding solvated forms. The compound of the invention may be truesolvates, while in other cases, the compound of the invention may merelyretain adventitious water or be a mixture of water plus someadventitious solvent.

Isotopes

Any formula or structure given herein, including Formula I, or anyFormula disclosed herein, is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as, but not limited to ²H (deuterium, D), ³H (tritium) ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl and ¹²⁵I. Various isotopicallylabeled compounds of the present disclosure, for example those intowhich radioactive isotopes such as ³H, ¹³C and ¹⁴C are incorporated.Such isotopically labeled compounds may be useful in metabolic studies,reaction kinetic studies, detection or imaging techniques, such aspositron emission tomography (PET) or single-photon emission computedtomography (SPECT) including drug or substrate tissue distributionassays or in radioactive treatment of patients.

The disclosure also includes compounds of Formula I, or any Formuladisclosed herein, in which from 1 to “n” hydrogens attached to a carbonatom is/are replaced by deuterium, in which n is the number of hydrogensin the molecule. Such compounds exhibit increased resistance tometabolism and are thus useful for increasing the half-life of anycompound of Formula I when administered to a mammal. See, for example,Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”,Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds aresynthesized by means well known in the art, for example by employingstarting materials in which one or more hydrogen atoms have beenreplaced by deuterium.

Deuterium labeled or substituted therapeutic compounds of the disclosuremay have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements. An18F labeled compound may be useful for PET or SPECT studies.Isotopically labeled compounds of this disclosure and prodrugs thereofcan generally be prepared by carrying out the procedures disclosed inthe schemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent. Further, substitution with heavierisotopes, particularly deuterium (i.e., 2H or D) may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements or animprovement in therapeutic index. It is understood that deuterium inthis context is regarded as a substituent in the compound of the FormulaI, or any Formula disclosed herein.

It is understood by one skilled in the art that this invention alsoincludes any compound claimed that may be enriched at any or all atomsabove naturally occurring isotopic ratios with one or more isotopes suchas, but not limited to, deuterium (²H or D). As a non-limiting example,in certain embodiments, a —CH₃ group is replaced with —CD₃.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

Specific values listed below for radicals, substituents, and ranges inthe embodiments of the invention are for illustration only; they do notexclude other defined values or other values within defined ranges forthe radicals and substituents.

II. Compounds

In some embodiments, disclosed herein is a compound of formula I:

-   wherein-   A is 3-6 membered carbocycle;-   n is 0, 1, or 2;-   m is 0, 1, or 2;-   R¹ is 5-12 membered heteroaryl or 5-12 membered heterocycle, wherein    any 5-12 membered heteroaryl or 5-12 membered heterocycle of R¹ is    unsubstituted or substituted with 1, 2, 3, 4 or 5 Z¹ groups, wherein    the Z¹ groups are the same or different;-   each Z¹ is independently (C₁-C₆)alkyl, (C₃-C₇)carbocycle, halogen,    or —CN, wherein any (C₁-C₆)alkyl or (C₃-C₇)carbocycle of Z¹ is    unsubstituted or substituted with 1, 2, 3, 4 or 5 Z^(1a) groups,    wherein the Z^(1a) groups are the same or different;-   each Z^(1a) is independently halogen, (C₃-C₇)carbocycle, —OH, or    —CN;-   R² is hydrogen, halogen, —OH, or —CN;-   R³ is (C₁-C₆)alkyl or 3-5 membered heterocycle, wherein the    (C₁-C₆)alkyl is unsubstituted or substituted with 1, 2, or 3 halogen    atoms;-   R⁴ is hydrogen, —S(O)₂—(C₁-C₆)alkyl, —S(O)₂—(C₃-C₆)carbocycle, or    5-6 membered heteroaryl, wherein any —S(O)₂—(C₁-C₆) alkyl,    —S(O)₂—(C₃-C₆)carbocycle, or 5-6 membered heteroaryl of R⁴ is    unsubstituted or substituted with 1, 2, or 3 Z² groups, wherein the    Z² groups are the same or different;-   Z² is (C₁-C₆)alkyl or (C₃-C₆)carbocycle, wherein any (C₁-C₆)alkyl or    (C₃-C₆)carbocycle is unsubstituted or substituted with 1, 2, or 3    Z^(2a) groups, wherein the Z^(2a) groups are the same or different;-   Z²a is hydroxyl or halogen;-   R⁵ is hydrogen or halogen; and-   R⁶ is (C₁-C₃)alkyl;-   or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is a compound of formula Ia:

-   wherein:-   n is 0, 1, or 2;-   m is 0 or 1;-   R¹ is 5-9 membered heteroaryl or 5-9 membered heterocycle, wherein    any 5-9 membered heteroaryl or 5-9 membered heterocycle of R¹ is    unsubstituted or substituted with 1, 2, 3, 4 or 5 Z¹ groups, wherein    the Z¹ groups are the same or different;-   each Z¹ is independently (C₁-C₆)alkyl, (C₃-C₇)carbocycle, or    halogen, wherein any (C₁-C₆)alkyl or (C₃-C₇)carbocycle of Z¹ is    unsubstituted or substituted with 1, 2, 3, 4 or 5 Z^(1a) groups,    wherein the Z^(1a) groups are the same or different;-   each Z^(1a) is independently halogen or (C₃-C₇)carbocycle;-   R² is hydrogen or iodide;-   R³ is (C₁-C₂)alkyl or 3-5 membered heterocycle, wherein the    (C₁-C₂)alkyl is unsubstituted or substituted with 2 or 3 halogen    atoms;-   R⁴ is hydrogen, —S(O)₂—(C₁-C₂)alkyl, —S(O)₂-cyclopropyl, or    5-membered heteroaryl, wherein any —S(O)₂—(C₁-C₂)alkyl,    —S(O)₂-cyclopropyl, or 5-membered heteroaryl of R⁴ is unsubstituted    or substituted with 1, 2, or 3 Z² groups, wherein the Z² groups are    the same or different;-   Z² is (C₁-C₃)alkyl or cyclopropyl, wherein any (C₁-C₃)alkyl or    cyclopropyl is unsubstituted or substituted with 1, 2, or 3 Z^(2a)    groups, wherein the Z^(2a) groups are the same or different;-   Z^(2a) is hydroxyl or fluorine;-   R⁵ is hydrogen, chorine, or fluorine; and-   R⁶ is (C₁-C₃)alkyl.

In some embodiments, disclosed herein is a compound of Formula (Ia), ora pharmaceutically acceptable salt thereof, wherein:

-   n is 0, 1, or 2;-   m is 0 or 1;-   R¹ is 5-9 membered heteroaryl that is unsubstituted or substituted    with 1, 2, 3, 4 or 5 Z¹ groups, wherein the Z¹ groups are the same    or different;-   each Z¹ is independently (C₁-C₆)alkyl, (C₃-C₇)carbocycle, or    halogen, wherein any (C₁-C₆)alkyl or (C₃-C₇)carbocycle of Z¹ is    unsubstituted or substituted with 1, 2, 3, 4 or 5 Z^(1a) groups,    wherein the Z^(1a) groups are the same or different;-   each Z^(1a) is independently halogen or (C₃-C₇)carbocycle;-   R² is hydrogen or iodide;-   R³ is (C₁-C₂)alkyl or 3-5 membered heterocycle, wherein the    (C₁-C₂)alkyl is unsubstituted or substituted with 2 or 3 fluorine    atoms;-   R⁴ is hydrogen, —S(O)₂—(C₁-C₂)alkyl, —S(O)₂-cyclopropyl, or    5-membered heteroaryl, wherein any —S(O)₂—(C₁-C₂)alkyl,    —S(O)₂-cyclopropyl, or 5-membered heteroaryl of R⁴ is unsubstituted    or substituted with 1, 2, or 3 Z² groups, wherein the Z² groups are    the same or different;-   Z² is (C₁-C₃)alkyl or cyclopropyl, wherein any (C₁-C₃)alkyl or    cyclopropyl is unsubstituted or substituted with 1, 2, or 3 Z^(2a)    groups, wherein the Z^(2a) groups are the same or different;-   Z^(2a) is hydroxyl or fluorine;-   R⁵ is hydrogen, chorine, or fluorine; and-   R⁶ is methyl.

In some embodiments, disclosed herein is a compound of Formula (Ia), ora pharmaceutically acceptable salt thereof, wherein:

-   n is 0, 1, or 2;-   m is 0 or 1;-   R¹ is 5-9 membered heteroaryl that is unsubstituted or substituted    with 1, 2, 3, 4 or 5 Z¹ groups, wherein the Z¹ groups are the same    or different;-   each Z¹ is independently (C₁-C₆)alkyl, (C₃-C₇)carbocycle, or    halogen, wherein any (C₁-C₆)alkyl or (C₃-C₇)carbocycle of Z¹ is    unsubstituted or substituted with 1, 2, 3, 4 or 5 Z^(1a) groups,    wherein the Z^(1a) groups are the same or different;-   each Z^(1a) is independently halogen or (C₃-C₇)carbocycle;-   R² is hydrogen or iodide;-   R³ is (C₁-C₂)alkyl or 4-membered heterocycle, wherein the    (C₁-C₂)alkyl is unsubstituted or substituted with 2 or 3 fluorine    atoms;-   R⁴ is —S(O)₂—(C₁-C₂)alkyl, —S(O)₂-cyclopropyl, or 5-membered    heteroaryl, wherein any —S(O)₂—(C₁-C₂)alkyl, —S(O)₂-cyclopropyl, or    5-membered heteroaryl of R⁴ is unsubstituted or substituted with 1,    2, or 3 Z² groups, wherein the Z² groups are the same or different;-   Z² is (C₁-C₃)alkyl or cyclopropyl, wherein any (C₁-C₃)alkyl or    cyclopropyl is unsubstituted or substituted with 1, 2, or 3 Z^(2a)    groups, wherein the Z^(2a) groups are the same or different;-   Z^(2a) is hydroxyl or fluorine;-   R⁵ is hydrogen, chorine, or fluorine; and-   R⁶ is methyl.

In some embodiments, disclosed herein is a compound of Formula (Ia), ora pharmaceutically acceptable salt thereof, wherein:

-   n is 0, 1, or 2;-   m is 0 or 1;-   R¹ is 5-9 membered heteroaryl that is unsubstituted or substituted    with 1, 2, 3, 4 or 5 Z¹ groups, wherein the Z¹ groups are the same    or different;-   each Z¹ is independently (C₁-C₆)alkyl, (C₃-C₇)carbocycle, or    halogen, wherein any (C₁-C₆)alkyl or (C₃-C₇)carbocycle of Z¹ is    unsubstituted or substituted with 1, 2, 3, 4 or 5 Z^(1a) groups,    wherein the Z^(1a) groups are the same or different;-   each Z^(1a) is independently halogen or (C₃-C₇)carbocycle;-   R² is hydrogen;-   R³ is (C₁-C₂)alkyl or 4 membered heterocycle, wherein the    (C₁-C₂)alkyl is unsubstituted or substituted with 2 or 3 fluorine    atoms;-   R⁴ is —S(O)₂—(C₁-C₂)alkyl, —S(O)₂-cyclopropyl, or 5-membered    heteroaryl, wherein any —S(O)₂—(C₁-C₂)alkyl, —S(O)₂-cyclopropyl, or    5-membered heteroaryl of R⁴ is unsubstituted or substituted with 1,    2, or 3 Z² groups, wherein the Z² groups are the same or different;    Z² is (C₁-C₃)alkyl or cyclopropyl, wherein any (C₁-C₃)alkyl or    cyclopropyl is unsubstituted or substituted with 1, 2, or 3 Z^(2a)    groups, wherein the Z^(2a) groups are the same or different;    Z²a is hydroxyl or fluorine;    R⁵ is hydrogen, chorine, or fluorine; and    R⁶ is methyl.

In some embodiments, a specific group of compounds of formula I arecompounds of formula (Ib):

or a pharmaceutically acceptable salt thereof.

In some embodiments, a specific group of compounds of formula I arecompounds of formula (Ic):

or a pharmaceutically acceptable salt thereof.

In some embodiments, a specific group of compounds of formula I arecompounds of formula (Id):

or a pharmaceutically acceptable salt thereof.

In some embodiments, a specific group of compounds of formula I arecompounds of formula (Ie):

whereineach X¹ and X² are independently N or CH;or a pharmaceutically acceptable salt thereof.

In some embodiments, a specific group of compounds of formula I arecompounds of formula (If):

wherein

X¹ is N or CH;

or a pharmaceutically acceptable salt thereof.

In some embodiments, a specific group of compounds of formula I arecompounds of formula (Ig):

whereinq is 0, 1, 2, or 3;each X¹, X², and X³ are independently N or CH;or a pharmaceutically acceptable salt thereof.

In some embodiments, a specific group of compounds of formula I arecompounds of formula (Ih):

whereinq is 0, 1, 2, or 3;each X² and X³ are independently N or CH;or a pharmaceutically acceptable salt thereof.

In some embodiments, a specific group of compounds of formula I arecompounds of formula (Ii):

whereinq is 0, 1, 2, or 3;each X² and X³ are independently N or CH;or a pharmaceutically acceptable salt thereof.

In some embodiments, a specific group of compounds of formula I arecompounds of formula (Ij):

whereinq is 0, 1, 2, or 3;each X¹, X², and X³ are independently N or CH;or a pharmaceutically acceptable salt thereof.

In some embodiments, a specific group of compounds of formula I arecompounds of formula (Ik):

whereineach X² and X³ are independently N or CH;or a pharmaceutically acceptable salt thereof.

Specific values listed below are values for compounds of formula I aswell as all related formulas (e.g., formulas I, Ia, Ib, Ic, Id, Ie, If,Ig, Ih, Ii, Ij and Ik). It is to be understood that two or more valuesmay combined. Thus, it is to be understood that any variable forcompounds of formula I may be combined with any other variable forcompounds of formula I the same as if each and every combination ofvariables were specifically and individually listed. For example, it isunderstood that any specific value of R¹ detailed herein for compoundsof formula I may be combined with any other specific value for one ormore of the variables, e.g., Z¹, Z², R², R³, R⁴, R⁵, R⁶ the same as ifeach and every combination were specifically and individually listed.

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein A is acyclopropyl group that is unsubstituted or substituted with 1 or 2 R⁶groups

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein n is 0.

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein n is 1.

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein n is 2.

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein n is 3.

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein m is 0.

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein m is 1.

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein 1Z¹ is:

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein 1Z¹ is:

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein 1Z¹ is:

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein 1Z¹ is:

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein R¹ is:

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein R¹ is:

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein R¹ is:

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein Z¹ is(C₁-C₆)alkyl substituted with 2 or 3 halogen atoms, a cyclopropyl group,or halogen.

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein Z¹ is—CHF₂, —CF₃, or halogen.

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein Z¹ is—CHF₂ or —CF₃.

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein R² ishydrogen or iodide.

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein R² ishydrogen.

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein R² isiodide.

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein R³ is(C₁₋₃)alkyl or a 4 membered heterocycle, wherein the (C₁₋₃)alkyl isunsubstituted or substituted with 1, 2, or 3 halogen atoms.

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein R³ ismethyl, —CH₂CHF₂, —CH₂CF₃, or

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein R³ ismethyl, —CH₂CHF₂, or —CH₂CF₃.

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein R⁴ ishydrogen, —S(O)₂—(C₁₋₆)alkyl, —S(O)₂—(C₃₋₆)carbocycle, or 5-6 memberedheteroaryl, wherein any —S(O)₂—(C₁₋₆)alkyl, —S(O)₂—(C₃₋₆)carbocycle, or5-6 membered heteroaryl of R⁴ is unsubstituted or substituted with 1, 2,or 3 Z² groups, wherein the Z² groups are the same or different.

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein R⁴ ishydrogen.

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein R⁴ is—S(O)₂—(C₁₋₂)alkyl, —S(O)₂-cyclopropyl, or 5-membered heteroaryl,wherein any —S(O)₂—(C₁₋₂)alkyl, —S(O)₂-cyclopropyl, or 5-memberedheteroaryl of R⁴ is unsubstituted or substituted with 1, 2, or 3 Z²groups, wherein the Z² groups are the same or different.

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein R⁴ is—S(O)₂—(C₁₋₂)alkyl, —S(O)₂-cyclopropyl, or an oxadiazole, wherein any—S(O)₂—(C₁₋₂)alkyl, —S(O)₂-cyclopropyl, or oxadiazole of R⁴ isunsubstituted or substituted with 1, 2, or 3 Z² groups, wherein the Z²groups are the same or different.

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein R⁴ is

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein R⁴ is

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein R⁴ is

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein R⁵ ishydrogen or halogen.

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein R⁵ ishydrogen, chloride, or fluoride.

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein R⁵ ischloride.

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein R⁶ ishydrogen or methyl.

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein m is 1and R⁶ is (C₁-C₃)alkyl.

In some embodiments, a specific group of compounds of formula I, or apharmaceutically acceptable salt thereof, are compounds wherein m is 1and R⁶ is methyl.

In some embodiments, the compound of formula I is selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I is selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I is selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I is:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I is selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I is selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I is selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I is selected from:

or a pharmaceutically acceptable salt thereof.

III. Combination Therapy

In some embodiments, the invention provides a method for preventing ortreating an HIV infection, comprising administering to a patient in needthereof a therapeutically effective amount of a compound disclosedherein, or a pharmaceutically acceptable salt thereof, in combinationwith a therapeutically effective amount of one or more additionaltherapeutic agents which are suitable for treating an HIV infection.

A compound as disclosed herein (e.g., a compound of any of formulas I,Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij and Ik, or a pharmaceuticallyacceptable salt thereof) may be combined with one or more additionaltherapeutic agents in any dosage amount of the compound (e.g., from 1 mgto 5 mg, 5 mg to 10 mg, 10 mg to 50 mg, 50 mg to 100 mg, 100 mg to 300mg).

In some embodiments, a method for treating or preventing an HIVinfection in a human having or at risk of having the infection isprovided, comprising administering to the human a therapeuticallyeffective amount of a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of one or more additional therapeutic agents.

In some embodiments, the invention provides pharmaceutical compositionscomprising a compound disclosed herein, or a pharmaceutically acceptablesalt thereof, in combination with at least one additional therapeuticagent, and a pharmaceutically acceptable carrier. For example, thetherapeutic agent used in combination with the compound disclosed hereincan be any anti-HIV agent.

In some embodiments, combination pharmaceutical agents comprising acompound disclosed herein, or a pharmaceutically acceptable saltthereof, in combination with one or more additional therapeutic agentsare provided.

In some embodiments, provided herein are pharmaceutical compositionscomprising a compound disclosed herein, or a pharmaceutically acceptablesalt thereof, in combination with at least one additional therapeuticagent, and a pharmaceutically acceptable carrier.

In some embodiments, the additional therapeutic agent may be an anti-HIVagent. For example, in some embodiments, the additional therapeuticagent is selected from the group consisting of HIV protease inhibitingcompounds (HIV protease inhibitors), HIV non-nucleoside inhibitors ofreverse transcriptase, HIV nucleoside inhibitors of reversetranscriptase, HIV nucleotide inhibitors of reverse transcriptase, HIVintegrase inhibitors, HIV non-catalytic site (or allosteric) integraseinhibitors, HIV entry inhibitors (e.g., CCR5 inhibitors, gp41 inhibitors(i.e., fusion inhibitors) and CD4 attachment inhibitors), CXCR4inhibitors, gp120 inhibitors, G6PD and NADH-oxidase inhibitors,additional capsid polymerization inhibitors or capsid disruptingcompounds such as those disclosed in US 2013/0165489 (University ofPennsylvania), and WO 2013/006792 (Pharma Resources), pharmacokineticenhancers, HIV maturation inhibitors, latency reversing agents,immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors,HIV antibodies, bispecific antibodies and “antibody-like” therapeuticproteins, HIV p17 matrix protein inhibitors, IL-13 antagonists,peptidyl-prolyl cis-trans isomerase A modulators, protein disulfideisomerase inhibitors, complement C5a receptor antagonists, DNAmethyltransferase inhibitor, HIV vif gene modulators, Vif dimerizationantagonists, HIV-1 viral infectivity factor inhibitors, TAT proteininhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixedlineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Revprotein inhibitors, integrin antagonists, nucleoprotein inhibitors,splicing factor modulators, COMM domain containing protein 1 modulators,HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors,dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG proteininhibitors, HIV POL protein inhibitors, Complement Factor H modulators,ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclindependent kinase inhibitors, proprotein convertase PC9 stimulators, ATPdependent RNA helicase DDX3X inhibitors, reverse transcriptase primingcomplex inhibitors, HIV gene therapy, HIV vaccines, and combinationsthereof.

In some embodiments, the additional therapeutic agent is selected fromimmunomodulators, immunotherapeutic agents, antibody-drug conjugates,gene modifiers, gene editors (such as CRISPR/Cas9, zinc fingernucleases, homing nucleases, synthetic nucleases, TALENs), and celltherapies such as chimeric antigen receptor T-cell, CAR-T (e.g.,YESCARTA® (axicabtagene ciloleucel)), and engineered T cell receptors,TCR-T.

In some embodiments, the additional therapeutic agent is selected fromthe group consisting of combination drugs for HIV, other drugs fortreating HIV, HIV protease inhibitors, HIV reverse transcriptaseinhibitors, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIVmaturation inhibitors, latency reversing agents, additional capsidinhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, andbispecific antibodies, and “antibody-like” therapeutic proteins, andcombinations thereof.

HIV Combination Drugs

Examples of combination drugs include ATRIPLA® (efavirenz, tenofovirdisoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®;rilpivirine, tenofovir disoproxil fumarate, and emtricitabine);STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, andemtricitabine); TRUVADA® (tenofovir disoproxil fumarate andemtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide andemtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, andrilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine,cobicistat, and elvitegravir); darunavir, tenofovir alafenamidehemifumarate, emtricitabine, and cobicistat; efavirenz, lamivudine, andtenofovir disoproxil fumarate; lamivudine and tenofovir disoproxilfumarate; tenofovir and lamivudine; tenofovir alafenamide andemtricitabine; tenofovir alafenamide hemifumarate and emtricitabine;tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine;tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, andelvitegravir; COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM®(LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); KALETRA® (ALTJVIA®;lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir, andlamivudine); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine;ABC+AZT+3TC); atazanavir and cobicistat; atazanavir sulfate andcobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat;dolutegravir and rilpivirine; dolutegravir and rilpivirinehydrochloride; dolutegravir, abacavir sulfate, and lamivudine;lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine;doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine,lamivudine, and tenofovir disoproxil; dolutegravir+lamivudine,lamivudine+abacavir+zidovudine, lamivudine+abacavir,lamivudine+tenofovir disoproxil fumarate,lamivudine+zidovudine+nevirapine, lopinavir+ritonavir,lopinavir+ritonavir+abacavir+lamivudine,lopinavir+ritonavir+zidovudine+lamivudine, tenofovir+lamivudine, andtenofovir disoproxil fumarate+emtricitabine+rilpivirine hydrochloride,lopinavir, ritonavir, zidovudine and lamivudine; Vacc-4x and romidepsin;and APH-0812.

Other HIV Drugs

Examples of other drugs for treating HIV include acemannan, alisporivir,BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, Prolastin, REP9, RPI-MN, VSSP, Hlviral, SB-728-T, 1,5-dicaffeoylquinic acid,rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy,BlockAide, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43,HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-8507, MK-8591, NOV-205,PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452,TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo, and VIR-576.

HIV Protease Inhibitors

Examples of HIV protease inhibitors include amprenavir, atazanavir,brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir,indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate,ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657(PPL-100), T-169, BL-008, and TMC-310911.

HIV Reverse Transcriptase Inhibitors

Examples of HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase include dapivirine, delavirdine, delavirdine mesylate,doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine,AIC-292, KM-023, PC-1005, and VM-1500.

Examples of HIV nucleoside or nucleotide inhibitors of reversetranscriptase include adefovir, adefovir dipivoxil, azvudine,emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil,tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX®and VIDEX EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine,apricitabine, censavudine, didanosine, elvucitabine, festinavir,fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine,OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, lamivudine,phosphazid, stavudine, zalcitabine, zidovudine, GS-9131, GS-9148, andKP-1461.

HIV Integrase Inhibitors

Examples of HIV integrase inhibitors include elvitegravir, curcumin,derivatives of curcumin, chicoric acid, derivatives of chicoric acid,3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid,aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeicacid phenethyl ester, derivatives of caffeic acid phenethyl ester,tyrphostin, derivatives of tyrphostin, quercetin, derivatives ofquercetin, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567,cabotegravir (long-acting injectable), diketo quinolin-4-1 derivatives,integrase-LEDGF inhibitor, ledgins, M-522, M-532, NSC-310217,NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173,NSC-699174, stilbenedisulfonic acid, T-169 and cabotegravir.

Examples of HIV non-catalytic site, or allosteric, integrase inhibitors(NCINI) include CX-05045, CX-05168, and CX-14442.

HIV Entry Inhibitors

Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCRSinhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120inhibitors, and CXCR4 inhibitors.

Examples of CCRS inhibitors include aplaviroc, vicriviroc, maraviroc,cenicriviroc, PRO-140, adaptavir (RAP-101), nifeviroc (TD-0232),anti-GP120/CD4 or CCRS bispecific antibodies, B-07, MB-66, polypeptideC25P, TD-0680, and vMIP (Haimipu).

Examples of gp41 inhibitors include albuvirtide, enfuvirtide,BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusioninhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer andsifuvirtide.

Examples of CD4 attachment inhibitors include ibalizumab and CADAanalogs

Examples of gp120 inhibitors include Radha-108 (receptol) 3B3-PE38,BanLec, bentonite-based nanomedicine, fostemsavir tromethamine,IQP-0831, and BMS-663068

Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide,and vMIP (Haimipu).

HIV Maturation Inhibitors

Examples of HIV maturation inhibitors include BMS-955176 andGSK-2838232.

Latency Reversing Agents

Examples of latency reversing agents include histone deacetylase (HDAC)inhibitors, proteasome inhibitors such as velcade, protein kinase C(PKC) activators, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, PMA,SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamicacid), IL-15, JQ1, disulfram, amphotericin B, and ubiquitin inhibitorssuch as largazole analogs, and GSK-343.

Examples of HDAC inhibitors include romidepsin, vorinostat, andpanobinostat.

Examples of PKC activators include indolactam, prostratin, ingenol B,and DAG-lactones.

HIV Capsid Inhibitors

Examples of additional capsid inhibitors include capsid polymerizationinhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7)inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors,AVI-621, AVI-101, AVI-201, AVI-301, and AVI-CAN1-15 series.

In some embodiments, examples of additional capsid inhibitors include:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the additional capsid inhibitor is selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the additional capsid inhibitor is:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the additional capsid inhibitor is:

or a pharmaceutically acceptable salt thereof.

Immune-Based Therapies

Examples of immune-based therapies include toll-like receptorsmodulators such as t1r1, t1r2, t1r3, t1r4, t1r5, t1r6, t1r7, t1r8, t1r9,t1r10, t1r11, t1r12, and t1r13; programmed cell death protein 1 (Pd-1)modulators; programmed death-ligand 1 (Pd-L1) modulators; IL-15agonists; DermaVir; interleukin-7; plaquenil (hydroxychloroquine);proleukin (aldesleukin, IL-2); interferon alfa; interferon alfa-2b;interferon alfa-n3; pegylated interferon alfa; interferon gamma;hydroxyurea; mycophenolate mofetil (MPA) and its ester derivativemycophenolate mofetil (MMF); ribavirin; rintatolimod, polymerpolyethyleneimine (PEI); gepon; rintatolimod; IL-12; WF-10; VGV-1;MOR-22; BMS-936559; CYT-107, interleukin-15/Fc fusion protein,normferon, peginterferon alfa-2a, peginterferon alfa-2b, recombinantinterleukin-15, RPI-MN, GS-9620, STING modulators, RIG-I modulators,NOD2 modulators, and IR-103.

Phosphatidylinositol 3-Kinase (PI3K) Inhibitors

Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib,CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib,perifosine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib,rigosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439,CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577,GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666,RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857,VS-5584, XL-765, and ZSTK-474.

Alpha-4/Beta-7 Antagonists

Examples of Integrin alpha-4/beta-7 antagonists include PTG-100,TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.

HIV Antibodies, Bispecific Antibodies, and “Antibody-Like” TherapeuticProteins

Examples of HIV antibodies, bispecific antibodies, and “antibody-like”therapeutic proteins include DARTs®, DUOBODIES®, BITES®, XmAbs®,TandAbs®, Fab derivatives, bnABs (broadly neutralizing HIV-1antibodies), BMS-936559, TMB-360, and those targeting HIV gp120 or gp41,antibody-Recruiting Molecules targeting HIV, anti-CD63 monoclonalantibodies, anti-GB virus C antibodies, anti-GP120/CD4, CCRS bispecificantibodies, anti-nef single domain antibodies, anti-Rev antibody,camelid derived anti-CD18 antibodies, camelid-derived anti-ICAM-1antibodies, DCVax-001, gp140 targeted antibodies, gp41-based HIVtherapeutic antibodies, human recombinant mAbs (PGT-121), ibalizumab,Immuglo, MB-66.

In some embodiments, examples of those targeting HIV in such a mannerinclude bavituximab, UB-421, C2F5, 2G12, C4E10, C2F5+C2G12+C4E10,8ANC195, 3BNC117, 3BNC60, 10-1074, PGT145, PGT121, PGT-151, PGT-133,MDX010 (ipilimumab), DH511, N6, VRC01 PGDM1400, A32, 7B2, 10E8, 10E8v4,CAP256-VRC26.25, DRVIA7, VRC-07-523, VRC-HIVMAB080-00-AB,VRC-HIVMAB060-00-AB, MGD-014 and VRC07. Example of HIV bispecificantibodies include MGD014.

Pharmacokinetic Enhancers

Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

Additional Therapeutic Agents

Examples of additional therapeutic agents include the compoundsdisclosed in WO 2004/096286 (Gilead Sciences), WO 2006/015261 (GileadSciences), WO 2006/110157 (Gilead Sciences), WO 2012/003497 (GileadSciences), WO 2012/003498 (Gilead Sciences), WO 2012/145728 (GileadSciences), WO 2013/006738 (Gilead Sciences), WO 2013/159064 (GileadSciences), WO 2014/100323 (Gilead Sciences), US 2013/0165489 (Universityof Pennsylvania), US 2014/0221378 (Japan Tobacco), US 2014/0221380(Japan Tobacco), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034(Boehringer Ingelheim), WO 2013/006792 (Pharma Resources), US20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences) and WO2013/091096 (Boehringer Ingelheim).

HIV Vaccines

Examples of HIV vaccines include peptide vaccines, recombinant subunitprotein vaccines, live vector vaccines, DNA vaccines, CD4-derivedpeptide vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV(vCP1521)/AIDSVAX B/E (gp120) (RV144), monomeric gp120 HIV-1 subtype Cvaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401),Vacc-4x, Vacc-05, VAC-3S, multiclade DNA recombinant adenovirus-5(rAd5), Pennvax-G, Pennvax-GP, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax,Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLC adjuvanted vaccines,TatImmune, GTU-multiHIV (FIT-06), gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin/ENV, TBC-M4,HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123,rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env CladeC+Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101,CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag/pol/nef/nev(HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env,Ad26.Mod.HIV vaccine, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001,ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001, and virus-like particlevaccines such as pseudovirion vaccine, CombiVlCHvac, LFn-p24 B/C fusionvaccine, GTU-based DNA vaccine, HIV gag/pol/nef/env DNA vaccine,anti-TAT HIV vaccine, conjugate polypeptides vaccine, dendritic-cellvaccines, gag-based DNA vaccine, GI-2010, gp41 HIV-1 vaccine, HIVvaccine (PIKA adjuvant), I i-key/MHC class II epitope hybrid peptidevaccines, ITV-2, ITV-3, ITV-4, LIPO-5, multiclade Env vaccine, MVAvaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine,recombinant peptide vaccine (HIV infection), NCI, rgp160 HIV vaccine,RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIVvaccine, UBI HIV gp120, Vacc-4x+romidepsin, variant gp120 polypeptidevaccine, rAd5 gag-pol env A/B/C vaccine, DNA.HTI and MVA.HTI.

HIV Combination Therapy

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents selected from ATRIPLA®(efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA®(EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, andemtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovirdisoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxilfumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamideand emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, andrilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine,cobicistat, and elvitegravir); adefovir; adefovir dipivoxil; cobicistat;emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxilfumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate;TRIUMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir,abacavir sulfate, and lamivudine; raltegravir; raltegravir andlamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®; lopinavir andritonavir); COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM®(LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (abacavirsulfate, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine;rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavirand cobicistat; darunavir and cobicistat; atazanavir; atazanavirsulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate andritonavir; darunavir; lamivudine; prolastin; fosamprenavir;fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavirmesylate; interferon; didanosine; stavudine; indinavir; indinavirsulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir;saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir;delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine andtenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovirdisoproxil fumarate; phosphazid; lamivudine, nevirapine, and zidovudine;abacavir; and abacavir sulfate.

It will be appreciated by one of skill in the art that the additionaltherapeutic agents listed above may be included in more than one of theclasses listed above. The particular classes are not intended to limitthe functionality of those compounds listed in those classes.

In some embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with an HIV nucleoside ornucleotide inhibitor of reverse transcriptase and an HIV non-nucleosideinhibitor of reverse transcriptase. In another specific embodiment, acompound disclosed herein, or a pharmaceutically acceptable saltthereof, is combined with an HIV nucleoside or nucleotide inhibitor ofreverse transcriptase, and an HIV protease inhibiting compound. In anadditional embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HIVnucleoside or nucleotide inhibitor of reverse transcriptase, an HIVnon-nucleoside inhibitor of reverse transcriptase, and a pharmacokineticenhancer. In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with at least oneHIV nucleoside inhibitor of reverse transcriptase, an integraseinhibitor, and a pharmacokinetic enhancer. In another embodiment, acompound disclosed herein, or a pharmaceutically acceptable saltthereof, is combined with two HIV nucleoside or nucleotide inhibitors ofreverse transcriptase.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with GS-9131,MK-8591, abacavir sulfate, bictegravir, tenofovir, tenofovir disoproxil,tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate,tenofovir alafenamide, or tenofovir alafenamide hemifumarate, or acombination thereof.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with bictegravir,GS-9131, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir alafenamide, or tenofovir alafenamide hemifumarate, or acombination thereof.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofabacavir sulfate, bictegravir, GS-9131, tenofovir, tenofovir disoproxil,tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofoviralafenamide hemifumarate, or a combination thereof, and a secondadditional therapeutic agent selected from the group consisting ofemtricitabine and lamivudine.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofbictegravir, GS-9131, tenofovir, tenofovir disoproxil, tenofovirdisoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamidehemifumarate, or a combination thereof, and a second additionaltherapeutic agent, wherein the second additional therapeutic agent isemtricitabine.

In some embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with 40-60 mg of bictegravir, 20-70mg GS-9131, 5-30 mg tenofovir alafenamide fumarate, tenofoviralafenamide hemifumarate, or tenofovir alafenamide and 200 mgemtricitabine. In some embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 1-3, 3-5,5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg tenofoviralafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofoviralafenamide and/or 200 mg emtricitabine. In some embodiments, a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, iscombined with 30-50, 50-75, 75-100; 100-150; 150-200; 250-300; 350-400;400-450; 450-500; or 500-550 mg tenofovir alafenamide fumarate,tenofovir alafenamide hemifumarate, or tenofovir alafenamide and/or 200mg emtricitabine. In some embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 500-750,750-1000, 1000-1500, 1500-2000, 2000-2500 mg tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamideand/or 200 mg emtricitabine. In some embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined with10 mg tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. In someembodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with 25 mg tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamideand 200 mg emtricitabine. In some embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined with50 mg of bictegravir. A compound as disclosed herein (e.g., a compoundof any of formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij and Ik, ora pharmaceutically acceptable salt thereof) may be combined with theagents provided herein in any dosage amount of the compound (e.g., from50 mg to 300 mg of compound) the same as if each combination of dosageswere specifically and individually listed.

In some embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with 200-400 mg tenofovirdisoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovirdisoproxil and 200 mg emtricitabine. In some embodiments, a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, iscombined with 200-250; 200-300; 200-350; 250-350; 250-400; 350-400;300-400; or 250-400 mg tenofovir disoproxil fumarate, tenofovirdisoproxil hemifumarate, or tenofovir disoproxil and and 200 mgemtricitabine. In some embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 300 mgtenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil and and 200 mg emtricitabine. A compound asdisclosed herein (e.g., a compound of any of formulas I, Ia, Ib, Ic, Id,Ie, If, Ig, Ih, Ii, Ij and Ik, or a pharmaceutically acceptable saltthereof) may be combined with the agents provided herein in any dosageamount of the compound (e.g., from 50 mg to 300 mg of compound) the sameas if each combination of dosages were specifically and individuallylisted.

In some embodiments, kits comprising a compound disclosed herein, or apharmaceutically acceptable salt thereof, in combination with one ormore (e.g., one, two, three, one or two, or one to three) additionaltherapeutic agents are provided. Birth control (contraceptive)combination therapy

Therapeutic agents used for birth control (contraceptive) includecyproterone acetate, desogestrel, dienogest, drospirenone, estradiolvalerate, ethinyl Estradiol, ethynodiol, etonogestrel, levomefolate,levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol,mifepristone, misoprostol, nomegestrol acetate, norelgestromin,norethindrone, noretynodrel, norgestimate, ormeloxifene, segestersoneacetate, ulipristal acetate, and any combinations thereof.

Gene Therapy and Cell Therapy

Gene Therapy and Cell Therapy including the genetic modification tosilence a gene; genetic approaches to directly kill the infected cells;the infusion of immune cells designed to replace most of the patient'sown immune system to enhance the immune response to infected cells, oractivate the patient's own immune system to kill infected cells, or findand kill the infected cells; genetic approaches to modify cellularactivity to further alter endogenous immune responsiveness against theinfection.

Examples of dendritic cell therapy include AGS-004.

Gene Editors

The genome editing system is selected from the group consisting of: aCRISPR/Cas9 system, a zinc finger nuclease system, a TALEN system, ahoming endonucleases system, and a meganuclease system.

Examples of HIV targeting CRISPR/Cas9 systems include EBT101.

CAR-T Cell Therapy

A population of immune effector cells engineered to express a chimericantigen receptor (CAR), wherein the CAR comprises an HIV antigen-bindingdomain. The HIV antigen include an HIV envelope protein or a portionthereof, gp120 or a portion thereof, a CD4 binding site on gp120, theCD4-induced binding site on gp120, N glycan on gp120, the V2 of gp120,the membrane proximal region on gp41. The immune effector cell is a Tcell or an NK cell. In some embodiments, the T cell is a CD4+ T cell, aCD8+ T cell, or a combination thereof.

Examples of HIV CAR-T include VC-CAR-T.

TCR-T Cell Therapy

TCR-T cells are engineered to target HIV derived peptides present on thesurface of virus-infected cells.

In some embodiments, one or more of the compounds disclosed herein arecombined with one or more other active therapeutic agents in a unitarydosage form for simultaneous or sequential administration to a patient.In certain embodiments, a pharmaceutical composition including one ormore of the compounds disclosed herein combined with one or more otheractive therapeutic agents is provided. In certain embodiments, thecompounds disclosed herein are combined with one or more other activetherapeutic agents in a solid dosage form. The combination therapy maybe administered as a simultaneous or sequential regimen. Whenadministered sequentially, the combination may be administered in two ormore administrations.

In some embodiments, one or more of the compounds disclosed herein areco-administered with one or more other active therapeutic agents.Co-administration of a compound disclosed herein with one or more otheractive therapeutic agents generally refers to simultaneous or sequentialadministration of a compound disclosed herein and one or more otheractive therapeutic agents, such that therapeutically effective amountsof disclosed herein and one or more other active therapeutic agents areboth present in the body of the patient.

In yet another embodiment, the present application provides a method fortreating an HIV infection comprising administering to a patient in needthereof a therapeutically effective amount of a compound disclosedherein, or a pharmaceutically acceptable salt thereof, in combinationwith a therapeutically effective amount of one or more additionaltherapeutic agents such as those disclosed above.

In some embodiments, the methods disclosed herein involve administrationprior to and/or after an event that would expose the individual to HIVor that would otherwise increase the individual's risk of acquiring HIV,e.g., as pre-exposure prophylaxis (PrEP) and/or as post-exposureprophylaxis (PEP). Examples of events that could increase anindividual's risk of acquiring HIV include, without limitation, nocondom use during anal intercourse with an HIV positive partner or apartner of unknown HIV status; anal intercourse with more than 3 sexpartners; exchange of money, gifts, shelter or drugs for anal sex; sexwith male partner and diagnosis of sexually transmitted infection; andno consistent use of condoms with sex partner known to be HIV positive.

IV. Pharmaceutical Formulations

The compounds disclosed herein are formulated with conventional carriers(e.g., inactive ingredient or excipient material) which will be selectedin accord with ordinary practice. Tablets will contain excipientsincluding glidants, fillers, binders and the like. Aqueous formulationsare prepared in sterile form, and when intended for delivery by otherthan oral administration generally will be isotonic. All formulationswill optionally contain excipients such as those set forth in theHandbook of Pharmaceutical Excipients (1986). Excipients includeascorbic acid and other antioxidants, chelating agents such as EDTA,carbohydrates such as dextrin, hydroxyalkylcellulose,hydroxyalkylmethylcellulose, stearic acid and the like. One embodimentprovides the formulation as a solid dosage form including a solid oraldosage form. The pH of the formulations ranges from about 3 to about 11,but is ordinarily about 7 to 10.

While it is possible for the active ingredients to be administered aloneit may be preferable to present them as pharmaceutical formulations(compositions). The formulations, both for veterinary and for human use,of the invention comprise at least one active ingredient, as abovedefined, together with one or more acceptable carriers and optionallyother therapeutic ingredients. The carrier(s) must be “acceptable” inthe sense of being compatible with the other ingredients of theformulation and physiologically innocuous to the recipient thereof.

The formulations include those suitable for the foregoing administrationroutes. The formulations may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. Techniques and formulations generally are found in Remington'sPharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methodsinclude the step of bringing into association the active ingredient withinactive ingredients (e.g., a carrier, pharmaceutical excipients, etc.)which constitutes one or more accessory ingredients. In general theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product.

Formulations described herein that are suitable for oral administrationmay be presented as discrete units including but not limited tocapsules, cachets or tablets each containing a predetermined amount ofthe active ingredient.

Pharmaceutical formulations disclosed herein comprise one or morecompounds disclosed herein together with one or more pharmaceuticallyacceptable carriers or excipients and optionally other therapeuticagents. Pharmaceutical formulations containing the active ingredient maybe in any form suitable for the intended method of administration. Whenused for oral use for example, tablets, troches, lozenges, aqueous oroil suspensions, dispersible powders or granules, emulsions, hard orsoft capsules, syrups or elixirs may be prepared. Compositions intendedfor oral use may be prepared according to any method known to the artfor the manufacture of pharmaceutical compositions and such compositionsmay contain one or more agents including sweetening agents, flavoringagents, coloring agents and preserving agents, in order to provide apalatable preparation. Tablets containing the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipient which aresuitable for manufacture of tablets are acceptable. These excipients maybe, for example, inert diluents, such as calcium or sodium carbonate,lactose, lactose monohydrate, croscarmellose sodium, povidone, calciumor sodium phosphate; granulating and disintegrating agents, such asmaize starch, or alginic acid; binding agents, such as cellulose,microcrystalline cellulose, starch, gelatin or acacia; and lubricatingagents, such as magnesium stearate, stearic acid or talc. Tablets may beuncoated or may be coated by known techniques includingmicroencapsulation to delay disintegration and adsorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax may be employed.

The amount of active ingredient that is combined with the inactiveingredients to produce a dosage form will vary depending upon the hosttreated and the particular mode of administration. For example, in someembodiments, a dosage form for oral administration to humans containsapproximately 1 to 1000 mg of active material formulated with anappropriate and convenient amount of carrier material (e.g., inactiveingredient or excipient material). In some embodiments, a dosage form(e.g., for oral administration to humans) contains: from 1 mg to 1000 mgor from 3 mg to 1000 mg or 5 mg to 1000 mg or 10 mg to 1000 mg or from50 mg to 1000 mg or from 100 mg to 1000 mg or from 200 mg to 1000 mg orfrom 300 mg to 1000 mg or from 10 mg to 800 mg or from 10 mg to 600 mgor from 10 mg to 500 mg or from 10 mg to 400 mg or from 10 mg to 300 mgor from 50 mg to 800 mg or from 100 mg to 600 mg or from 150 mg to 500mg or from 200 mg to 400 mg or from 50 mg to 500 mg or from 10 mg to 300mg or from 50 mg to 300 mg or from 10 mg to 200 mg or from 50 mg to 200mg or from 100 mg to 300 mg or from 100 mg to 200 mg or from 200 mg to300 mg of active material (e.g., a compound of any of formulae I, Ia,Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij and Ik, or a pharmaceuticallyacceptable salt thereof). In some embodiments, a dosage form for oraladministration to humans contains at least any of 1, 3, 5, 10, 25, 50,100, 150, 200, 250 or 300 mg and no more than 500 or 800 or 1000 mg ofactive material (e.g., from at least 50 mg to no more than 500 mg). Insome embodiments, a dosage form for oral administration to humanscontains at least any of 1, 3, 5, 10, 25, 50, 100, 150, 200, 250 or 300mg or no more than 500 or 800 or 1000 mg of active material. In someembodiments, a dosage form for oral administration to humans containsany of 1, 3, 5, 10, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500,550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of activematerial. It is understood that a dosage form in an amount providedherein may be administered to a patient (e.g., a human in need thereof)in accordance with a dosing regimen provided herein, such as once, twiceor thrice daily dosing. In one aspect, a dosing regimen provides foradministration of at least 10 mg and no more than 1,000 mg of activematerial (e.g., a compound of any of formulas I, Ia, Ib, Ic, Id, Ie, If,Ig, Ih, Ii, Ij and Ik, or a pharmaceutically acceptable salt thereof)daily, and it is understood that the amount may be provided in anysuitable dosage form and amount (e.g., 500 mg twice daily or 1,000 mgonce daily would provide the same amount of 1,000 mg/day dosing). Theinvention embraces once daily dosing to an individual (e.g., a human inneed thereof) of a dosage form of compound (e.g., a compound of any offormulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij and Ik, or apharmaceutically acceptable salt thereof) containing at least 50 mg andnot more than 300 mg of compound. In certain embodiments, the carriermaterial varies from about 5 to about 95% of the total compositions(weight: weight).

It should be understood that in addition to the ingredients particularlymentioned above the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

The invention further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier.

Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

Effective dose of active ingredient depends at least on the nature ofthe condition being treated, toxicity, whether the compound is beingused prophylactically (lower doses), the method of delivery, and thepharmaceutical formulation, and will be determined by the clinicianusing conventional dose escalation studies.

V. Routes of Administration

One or more compounds disclosed herein (herein referred to as the activeingredients) are administered by any route appropriate to the conditionto be treated. Suitable routes include oral, rectal, nasal, topical(including buccal and sublingual), vaginal and parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intrathecal andepidural), and the like. In some embodiments, one or more compoundsdisclosed herein are administered parenterally (e.g., subcutaneous,intramuscular). It will be appreciated that the preferred route may varywith for example the condition of the recipient.

VI. Dosing Regimen

The compound, such as a compound of any of Formulas I, Ia, Ib, Ic, Id,Ie, If, Ig, Ih, Ii, Ij and Ik, may be administered to an individual inaccordance with an effective dosing regimen for a desired period of timeor duration, such as daily (QD, BID, TID, etc.), at least about onemonth, at least about 2 months, at least about 3 months, at least about6 months, or at least about 12 months or longer. In one variation, thecompound is administered on a daily or intermittent schedule for theduration of the individual's life.

The dosage or dosing frequency of a compound of any of Formulas I, Ia,Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij and Ik, may be adjusted over thecourse of the treatment, e.g., based on the judgment of theadministering physician.

The compound may be administered to an individual (e.g., a human) in aneffective amount. In one aspect, the compound is administered oncedaily. In one aspect, the compound is administered twice a day. In oneaspect, the compound is administered three times daily. It is understoodthat the compound may be administered in any dosage amount providedherein, such as a dosage amount that would provide at least 10 mg/daydosing and no more than 1,000 mg/day dosing. Once daily oral dosing isembraced, such as by administering a dosage form containing from 50 mgto 300 mg of compound.

VII. Methods and Examples

Synthesis of certain compounds and intermediates used to preparecompounds, are detailed in the following sections.

Abbreviations

The following is a list of abbreviations and acronyms used throughoutthe application:

Abbreviation Meaning ° C. Degree Celsius CH₃CN Acetonitrile d Doublet ddDoublet of doublets DCE 1,2-dichloroethane DCM Dichloromethane DEADDiethyl azodicarboxylate DIAD Diisopropyl azodicarboxylate DIPEA/DIEAN,N-diisopropylethylamine DMAP 4-dimethylaminopyridine DME1,2-dimethoxyethane DMF Dimethylformamide DMSO Dimethylsulfoxideequiv/eq Equivalents ESI Electrospray ionization Ac Acetate Et Ethyl gGrams HATU 2-(7-Aza-1H-Benzotriazole-1-yl)-1,1,3,3- tetramethyluroniumhexafluorophosphate HPLC High-performance liquid chromatography h/hrHours Hz Hertz J Coupling constant Kg Kilogram L Liter M Molar mmultiplet m/z mass-to-charge ratio M+ Mass peak M + H Mass peak plushydrogen mg Milligram MHz Megahertz min/m Minute ml/mL Milliliter mMMillimolar mmol Millimole MS Mass spectroscopy mol Mole NMR Nuclearmagnetic resonance Ph Phenyl ppm Parts per million RP Reverse phaseRT/rt Room temperature s Singlet t Triplet NEt₃ Triethylamine TFATrifluoroacetic acid TH Tetrahydrofuran TLC Thin layer chromatographyTMS trimethylsilyl δ Chemical shift μg Microgram μL/μl Microliter μMMicromolar μm Micrometer μmol Micromole

Example numbers for reactions or compounds are listed for convenience.

When production of starting materials is not particularly described, thecompounds are known or may be prepared analogously to methods known inthe art or as disclosed in the Examples. One of skill in the art willappreciate that synthetic methodologies described herein are onlyrepresentative of methods for preparation of the compounds describedherein, and that other known methods and variants of methods describedherein may be used. The methods or features described in variousExamples may be combined or adapted in various ways to provideadditional ways of making the compounds described herein.

General Synthetic Procedures

The following schemes describe methods that are useful for preparingcompounds of formula I (e.g., compounds of formula Ia). For example, asdetailed below, compounds of formula I may be prepared using GeneralScheme 1, General Scheme 2, General Scheme 3, and/or General Scheme 4.

Scheme 1 describes a general stereoselective route that is used toprepare compounds of Formula I (e.g., compounds 1.15 and 1.16).Heteroaryl aldehydes of formula 1.1 (where X represents diversifiablechemical group such as NH₂, SH, or halogen that are suitably protected)are condensed with chiral auxiliary (S)-tert-butane sulfinamide followedby stereoselective addition of a nucleophilic Grignard reagent toprovide a mixture of 1.3 and 1.4 enriched in 1.3. This mixture isseparated by column chromatography on silica gel to provide purediastereomers. Removal of the auxiliary provides amines 1.5 and 1.6which are protected. Sequential diversification of 1.7 and 1.8 isaccomplished by a variety of methods including alkylation, acylation,cyanation, nucleophilic aromatic displacement, and metal catalyzed crosscoupling reactions such as Suzuki couplings, Buchwald-Hartwig typecouplings, and Sonogashira couplings. Lastly, the BOC protecting groupis removed and the resultant amines are coupled to a variety ofcarboxylic acids to provide heteroaryl compounds of formula 1.15 and1.16.

Scheme 2 describes a general stereoselective route that is used toprepare compounds of Formula 2.6 from intermediate 2.1. For example,compound 2.1 can be converted into compound 2.3 through a variety ofmethods such as metal catalyzed coupling reactions (e.g., Suzukicouplings, Buchwald-Hartwig type couplings, and Sonogashira couplings).Compound 2.3, in turn, can be converted into compound 2.6 through anN-alkylation reaction followed by BOC-deprotection and amide formation.

Scheme 3 describes a general stereoselective route that is used toprepare compounds of Formula 3.5 from intermediate 3.1. For example,compounds 3.1 (where R⁴ is not H) and 3.2 are reacted to give compoundsof formula 3.3 via a metal catalyzed coupling reaction (e.g., Suzukicouplings). Deprotection of 3.3 is followed by amide formation to givecompounds of formula 3.5.

Scheme 4 describes a general stereoselective route that is used toprepare compounds of Formula 4.5.

Scheme 5 describes a general route that is used to prepare compounds ofFormula 5.4.

Scheme 6 describes a general route that is used to prepare compounds ofFormula 6.2.

Example Procedures of Intermediates and Compound Examples

Methods for obtaining the novel compounds described herein will beapparent to those of ordinary skill in the art, with suitable proceduresbeing described, for example, in the reaction schemes and examplesbelow, and in the references cited herein.

While the foregoing description describes specific embodiments andaspects, those with ordinary skill in the art will appreciate thatvarious modifications and alternatives can be developed. Accordingly,the particular embodiments and aspects described above are meant to beillustrative only, and not to limit the scope of the present disclosure,which is to be given the full breadth of the appended claims, and anyand all equivalents thereof. Each of the foregoing references are herebyincorporated by reference.

The following Examples are illustrative of syntheses carried out withinthe context of the General Schemes above.

Example 1

Synthesis of 7-bromo-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-amine(1B)

To a 2000-mL 4-necked round-bottom flask was placed7-bromo-4-chloro-1H-indazol-3-amine (130 g, 527.40 mmol, 1.00 equiv),N,N-dimethylformamide (1300 mL), Cs₂CO₃ (260 g, 797.99 mmol, 1.50 equiv)with stirring for 20 min, followed by the addition of1,1-difluoro-2-iodoethane (122 g, 635.59 mmol, 1.20 equiv). Theresulting mixture was stirred overnight at 65° C., then cooled to roomtemperature, quenched by the addition of 3 L of water/ice, extractedwith 3×1.5 L of ethyl acetate. The combined organic layer was washedwith 1×1.5 L of H₂O, 1×1.5 L of brine, dried over anhydrous sodiumsulfate and concentrated under vacuum, and recrystallized from ethanolto afford 7-bromo-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-amine.

Synthesis of4-chloro-1-(2,2-difluoroethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine(1C)

To a 3000-mL 4-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen was placed7-bromo-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-amine (80 g, 257.63mmol, 1.00 equiv), 1,4-dioxane (800 mL), N,N-dimethylformamide (800 mL),KOAc (76 g, 774.40 mmol, 3.00 equiv),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(197 g, 775.78 mmol, 3.00 equiv) and Pd(PPh₃)₂Cl₂ (8 g, 11.40 mmol, 0.04equiv). The mixture was stirred for 4 h at 110° C., then cooled to roomtemperature, quenched by the addition of 5 L of water/ice, extractedwith 2×2 L of ethyl acetate. The combined organic layer was washed with1×1 L of H₂O, 1×1 L of brine, dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn eluted with ethyl acetate/petroleum ether (1:10) to afford4-chloro-1-(2,2-difluoroethyl)-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine.MS (m/z): 358 [M+H]⁺. (DMSO-d6, 300 MHz, ppm): δ7.63-7.66 (1H, d),7.00-7.03 (1H, d), 6.06-6.43 (1H, t), 5.46 (2H, s), 4.90-5.01 (2H, t),1.34 (12H, s).

Synthesis of ((2-methylbut-3-yn-2-yl)sulfonyl)cyclopropane (1E)

To a suspension of sodium cyclopropanesulfinate and copper chloride inDMF, 3-chloro-3-methylbut-1-yne was added to the suspension slowly. Itwas stirred at 40° C. overnight. The mixture was diluted with ethylacetate and washed with 5% LiCl and brine. The organic layer was driedand concentrated and purified by silica gel chromatography. ¹H NMR (400MHz, Chloroform-d) δ 2.71 (tt, 1H), 1.68 (s, 6H), 1.36-1.26 (m, 2H),1.21-1.01 (m, 2H).

Synthesis of tert-butyl(S)-(1-(3-bromo-6-(3-(cyclopropylsulfonyl)-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(1G)

A round bottom flask was charged with tert-butyl(S)-(1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(5 g, 10.16 mmol) synthesized as described in WO2014/134566,((2-methylbut-3-yn-2-yl)sulfonyl)cyclopropane (2.54 g, 14.73 mmol),Bis(triphenylphosphine)palladium(II) dichloride (214 mg, 0.31 mmol) andcopper(I) iodide (58 mg, 0.31 mmol). DMF (dimethylformamide) (6 mL) andEt₃N (trimethylamine) (5.7 mL, 40.64 mmol) were added. The reactionmixture was degassed and purged with argon then heated to 50° C. for 40minutes. It was partitioned between EtOAc and 5% LiCl aqueous solution.The organic layer was separated and washed with NH4Cl (sat′d) and brine,dried over MgSO₄, filtered and concentrated to afford crude product. Itwas purified by silica gel chromatography eluting with EtOAc/hexanes toafford the title compound. MS (m/z):584.79 [M+H]⁺.

Synthesis of tert-butyl(S)-(1-(3-(3-amino-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-6-(3-(cyclopropylsulfonyl)-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(1H)

tert-butyl(S)-(1-(3-bromo-6-(3-(cyclopropylsulfonyl)-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(1000.0 mg, 1.71 mmol),4-chloro-1-(2,2-difluoroethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine(796.7 mg, 2.23 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (43.33 mg,0.051 mmol), and potassium carbonate (592 mg, 4.29 mmol) were charged ina microwave tube and placed under argon. Dimethoxyethane (12 mL) andwater (2 mL) were added, and the suspension was degassed by bubblingargon for 60 seconds. After degassing the reaction mixture was heated to125° C. in a microwave reactor (Biotage® Initiator+) for 20 minutes, andthe reaction mixture was cooled to room temperature. It was partitionedbetween EtOAc and 0.1 N HCl. the aqueous layer was removed. The organiclayer was concentrated under vacuum, and the resulting residue waspurified by silica gel column chromatography to provide the titlecompound. MS (m/z) 734.49 [M+H]⁺).

Synthesis of tert-butyl(S)-(1-(3-(4-chloro-1-(2,2-difluoroethyl)-3-(N-(methylsulfonyl)methylsulfonamido)-1H-indazol-7-yl)-6-(3-(cyclopropylsulfonyl)-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (H)

tert-butyl(S)-(1-(3-(3-amino-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-6-(3-(cyclopropylsulfonyl)-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(300 mg, 0.41 mmol) was dissolved in methylene chloride (6 mL) withstirring at ambient temperature. To it was addedN,N-Diisopropylethylamine (0.21 mL, 1.23 mmol) followed by slow additionof methanesulfonyl chloride (0.063 mL, 0.82 mmol). When the reaction wascomplete, water was added and stirred for 0.5 hours. The organic layerwas separated and the aqueous layer was extracted with methylenechloride once. The combined organic layers were washed with water andbrine, dried over MgSO₄, filtered and concentrated. The residue waspurified by silica gel column chromatography to provide the titlecompound. MS (m/z) 890.01 [M+H]⁺).

Synthesis of(S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-(cyclopropylsulfonyl)-3-methylbut-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)-N-(methylsulfonyl)methanesulfonamide(1J)

To tert-butyl(S)-(1-(3-(4-chloro-1-(2,2-difluoroethyl)-3-(N-(methylsulfonyl)methylsulfonamido)-1H-indazol-7-yl)-6-(3-(cyclopropylsulfonyl)-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (288 mg, 0.32 mmol) dissolved inmethylene chloride (3 mL) was added trifluoroacetic acid (1 mL). Thereaction mixture was stirred at ambient temperature for 30 minutes. Thesolvent was removed to afford the title compound as TFA salt. MS (m/z):790.28 [M+H]+).

Synthesis ofN—((S)-1-(3-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-(cyclopropylsulfonyl)-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(1M)

(S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-(cyclopropylsulfonyl)-3-methylbut-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)-N-(methylsulfonyl)methanesulfonamide(115 mg, 0.13 mmol),2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid (36.57 mg, 0.13 mmol), and HATU(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) (59.13 mg, 0.16 mmol) were charged in around bottom flask and dissolved in DMF (dimethylformamide) (3 mL). Tothe solution was added N,N-diisopropylethylamine (0.11 mL, 0.65 mmol).After addition was complete, the reaction mixture was stirred at roomtemperature for 15 minutes to provide the intermediate 1 L which was notisolated (MS (m/z) 1054.75 [M+H]⁺). To the solution was added 1 mLethanol and 2 drops of 15% of sodium hydroxide solution. The mixture wasstirred at room temperature for 30 minutes. The reaction mixture waspartitioned between water and ethyl acetate. The organic layer wascollected and washed with two portions of 5% lithium chloride solutionfollowed by brine. The organic layer was isolated, dried over sodiumsulfate, filtered, and concentrated under vacuum. The resulting residuewas purified by RP-HPLC to yield the title compound. MS (m/z) 976.22[M+H]⁺. ¹H NMR (400 MHz, Methanol-d₄) δ 8.86 (d), 8.73 (d), 7.79 (d),7.72 (d), 7.65 (dd), 7.20 (q), 7.13 (d), 6.83-6.72 (m), 6.72-6.61 (m),6.52 (d), 6.43 (dd), 6.36-6.25 (m), 6.21-5.51 (m), 5.05 (q), 4.93-4.62(m), 4.35-4.11 (m), 3.91-3.38 (m), 3.24 (s), 3.07 (ddd), 3.02-2.89 (m),2.85 (d), 2.68-2.36 (m), 1.84 (s), 1.47-1.35 (m), 1.36-1.18 (m),1.17-0.98 (m), 2.35 (m), 1.82 (s), 1.48-1.24 (m), 1.21-0.79 (m).

Example 2

Synthesis ofN-(4-chloro-1-(2,2-difluoroethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)-1-methylcyclopropane-1-sulfonamide(2A)

At 0° C., to mixture of4-chloro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine(1.5 g, 0.005 mol) in pyridine (10 mL) was added DMAP (0.119 g, 0.001mol) and followed by the addition of 1-methylcyclopropane-1-sulfonylchloride (2.262 g, 0.015 mol) in DCM (10 mL). The mixture was stirred at120° C. for 12 hr. The solvent was removed under vacuum and residue wasdiluted with EtOAc (20 mL) and acidified with HCl(2N). The organic phasewas washed with H₂O and brine and dried with MgSO₄. Solvent was removedunder vacuum. 2 ml EtOAc was added and the solid was filtered to obtainthe title product.

Synthesis of tert-butyl(S)-(1-(3-(4-chloro-1-(2,2-difluoroethyl)-3-((1-methylcyclopropane)-1-sulfonamido)-1H-indazol-7-yl)-6-(3-(cyclopropylsulfonyl)-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(2C)

A round bottom flask was charged withN-(4-chloro-1-(2,2-difluoroethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)-1-methylcyclopropane-1-sulfonamide(98 mg, 0.206 mmol), tert-butyl(S)-(1-(3-bromo-6-(3-(cyclopropylsulfonyl)-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(100 mg, 0.17 mmol), dichlorobis(tricyclohexlphosphine)palladium(II)(5.7 mg) and dioxane (1.5 mL), 1N solution of sodium bicarbonate inwater (0.4 mL) were added. The reaction mixture was degased and purgedwith argon then heated to 140° C. for 15 minutes. It was partitionedbetween EtOAc and aqueous solution. The organic layer was separated andwashed with brine, dried over MgSO₄, filtered and concentrated to affordcrude product. It was purified by silica gel chromatography eluting withEtOAc/hexanes to afford the title compound. MS (m/z):853.8 [M+H]⁺.

Synthesis of(S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-(cyclopropylsulfonyl)-3-methylbut-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)-1-methylcyclopropane-1-sulfonamide(2D)

Into the solution of tert-butyl(S)-(1-(3-(4-chloro-1-(2,2-difluoroethyl)-3-((1-methylcyclopropane)-1-sulfonamido)-1H-indazol-7-yl)-6-(3-(cyclopropylsulfonyl)-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(135 mg, 0.16 mmol) in methylene chloride (3 mL) was addedtrifluoroacetic acid (1 mL). The reaction mixture was stirred at ambienttemperature for 60 minutes. The solvent was removed, then it waspartitioned between EtOAc and sodium bicarbonate aqueous solution. Theorganic layer was separated and washed with brine, dried over MgSO₄,filtered and concentrated to afford crude product. MS (m/z): 754.11[M+H]⁺.

Synthesis ofN—((S)-1-(3-(4-chloro-1-(2,2-difluoroethyl)-3-((1-methylcyclopropane)-1-sulfonamido)-1H-indazol-7-yl)-6-(3-(cyclopropylsulfonyl)-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(2F)

Into the solution of(S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-(cyclopropylsulfonyl)-3-methylbut-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)-1-methylcyclopropane-1-sulfonamide(80 mg, 0.106 mmol) and 2,5-dioxopyrrolidin-1-yl2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate(46 mg, 0.128 mmol) in MeCN (5 ml), was added TEA (22 mg, 0.213 mmol) atroom temperature. After 2h, the reaction mixture was partitioned betweenwater and ethyl acetate. The organic layer was collected and washed withbrine. The organic layer was isolated, dried over sodium sulfate,filtered, and concentrated under vacuum. The resulting residue waspurified by RP-HPLC to yield 100 mg of title compound. MS (m/z) 1000.12[M+H]⁺. ¹H NMR (400 MHz, Methanol-d₄) δ 8.86 (d), 7.86-7.61 (m),7.31-7.07 (m), 6.89-6.65 (m), 6.50-6.27 (m), 6.09-5.67 (m), 4.90 (s),4.83-4.67 (m), 4.29-4.02 (m), 3.68 (s), 3.09 (dd), 3.02-2.90 (m),2.54-2.41 (m), 1.84 (s), 1.72 (d), 1.63 (s), 1.40 (d), 1.33-1.27 (m),1.27-1.18 (m), 1.06 (d), 0.76 (d).

Example 3

Synthesis ofN—((S)-1-(3-(3-amino-4-chloro-1-methyl-1H-indazol-7-yl)-6-(3-(cyclopropylsulfonyl)-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(3C)

To a solution of(S)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-(cyclopropylsulfonyl)-3-methylbut-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-amine(3A, synthesized according to procedures described in Example 1, 26.0mg, 0.045 mmol) in MeCN (3 mL) was added trimethylamine (31 μL, 0.22mmol) followed by 2,5-dioxopyrrolidin-1-yl2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate(3B, 23.6 mg, 0.062 mmol). The reaction mixture was stirred at roomtemperature for 30 minutes, then concentrated to provide crude 3C whichwas used without additional purification. MS (m/z) 848.16 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(4-chloro-3-isothiocyanato-1-methyl-1H-indazol-7-yl)-6-(3-(cyclopropylsulfonyl)-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(3D)

To a solution of crude 3C (37.8 mg, 0.045 mmol) in DCM (1.0 mL) andsaturated aqueous sodium bicarbonate (1.0 mL) was added thiophosgene(6.8 μL, 0.089 mmol). The reaction mixture was stirred at roomtemperature for 30 minutes. The organic layer was isolated, and theaqueous layer was extracted with an additional portion of DCM (1.0 mL).The combined organic layers were dried over sodium sulfate, filtered,and concentrated in vacuo. The resulting residue was purified by silicagel column chromatography to provide the title compound. MS (m/z) 890.09[M+H]⁺.

Synthesis ofN—((S)-1-(3-(4-chloro-3-(2-(2-hydroxy-2-methylpropanoyl)hydrazine-1-carbothioamido)-1-methyl-1H-indazol-7-yl)-6-(3-(cyclopropylsulfonyl)-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(3E)

To a solution ofN—((S)-1-(3-(4-chloro-3-isothiocyanato-1-methyl-1H-indazol-7-yl)-6-(3-(cyclopropylsulfonyl)-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-43bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(3D, 23.6 mg, 0.027 mmol) in THF (1.5 mL) was added2-hydroxy-2-methylpropanohydrazide (4.7 mg, 0.040 mmol). The reactionmixture was stirred at room temperature for 2 hours. The reactionmixture was concentrated in vacuo to provide crude title compound whichwas used without additional purification. MS (m/z) 1008.20 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(4-chloro-3-((5-(2-hydroxypropan-2-yl)-1,3,4-oxadiazol-2-yl)amino)-1-methyl-1H-indazol-7-yl)-6-(3-(cyclopropylsulfonyl)-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(3F)

To a solution of crudeN—((S)-1-(3-(4-chloro-3-(2-(2-hydroxy-2-methylpropanoyl)hydrazine-1-carbothioamido)-1-methyl-1H-indazol-7-yl)-6-(3-(cyclopropylsulfonyl)-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(3E, 26.7 mg, 0.027 mmol) in DMF was added triethylamine (0.030 mL, 0.21mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (16.5mg, 0.11 mmol). The reaction mixture was stirred at room temperatureovernight then filtered and directly purified by reverse phase HPLC toprovide the title compound. MS (m/z) 974.23 [M+H]⁺. ¹H NMR (400 MHz,Methanol-d₄) δ 8.90-8.82 (m), 7.80-7.72 (m), 7.68-7.58 (m), 7.22 (d),7.16 (d), 7.11 (s), 7.09 (s), 6.83-6.73 (m), 6.70-6.61 (m), 6.52 (s),6.50 (s), 6.47-6.38 (m), 5.40-5.23 (m), 5.10-4.98 (m), 4.78 (s), 4.77(s), 3.35 (s), 3.23-3.15 (m), 3.07-2.91 (m), 2.59-2.39 (m), 1.84 (s),1.84 (s), 1.64-1.56 (m), 1.50-1.36 (m), 1.35-1.21 (m), 1.20-1.01 (m).

Compound Table Compound General Procedure Example used for CompoundStructure Number Synthesis

1M 2

2F 3

3F 4

4 2

5 2

6 2

7 2

8 2

9 3

10 4

11 3

12 3

13 3

14 3

15 3

16 2

17 2

18 2

19 2

20 3

21 3

22 3

23 2

24 4

25 4

26 3

27 3

28 4

29 3

30 4

31 3

32 2

33 2

34 3

35 2

36 2

37 3

38 3

39 3

40 3

41 —

42 2

43 3

44 3

45 3

46 3

47 3

48 3

49 3

50 3

51 2

52 2

53 3

54 3

55 3

56 3

57 2

58 3

59 3

60 3

61 3

62 3

63 3

64 3

65 3

66 3

67 2

68 2

69 2

Characterization Table Example ES/MS (m/z) ¹H NMR   1M 976.2 1H NMR (400MHz, Methanol-d4) δ 8.86 (d), 8.73 (d), 7.79 (d), 7.72 (d), 7.65 (dd),7.20 (q), 7.13 (d), 6.83-6.72 (m), 6.72-6.61 (m), 6.52 (d), 6.43 (dd),6.36-6.25 (m), 6.21-5.51 (m), 5.05 (q), 4.93-4.62 (m), 4.35-4.11 (m),3.91-3.38 (m), 3.24 (s), 3.07 (ddd), 3.02-2.89 (m), 2.85 (d), 2.68-2.36(m), 1.84 (s), 1.47-1.35 (m), 1.36-1.18 (m), 1.17-0.98 (m), 2.35 (m),1.82 (s), 1.48-1.24 (m), 1.21-0.79 (m).  2F 998.2 1H NMR (400 MHz,Methanol-d4) δ 8.86 (d), 7.86-7.61 (m), 7.31-7.07 (m), 6.89-6.65 (m),6.50-6.27 (m), 6.09-5.67 (m), 4.90 (s), 4.83-4.67 (m), 4.29-4.02 (m),3.68 (s), 3.09 (dd), 3.02-2.90 (m), 2.54-2.41 (m), 1.84 (s), 1.72 (d),1.63 (s), 1.40 (d), 1.33-1.27 (m), 1.27-1.18 (m), 1.06 (d), 0.76 (d). 3F 974.2 1H N MR (400 MHz, Methanol-d4) δ 8.90-8.82 (m), 7.80-7.72 (m),7.68-7.58 (m), 7.22 (d), 7.16 (d), 7.11 (s), 7.09 (s), 6.83-6.73 (m),6.70-6.61 (m), 6.52 (s), 6.50 (s), 6.47-6.38 (m), 5.40-5.23 (m),5.10-4.98 (m), 4.78 (s), 4.77 (s), 3.35 (s), 3.23-3.15 (m), 3.07-2.91(m), 2.59-2.39 (m), 1.84 (s), 1.84 (s), 1.64-1.56 (m), 1.50-1.36 (m),1.35-1.21 (m), 1.20-1.01 (m).  4 908.7 1H NMR (400 MHz, Methanol-d4) δ8.72 (dd), 7.74 (t), 7.61 (dd), 7.25-7.14 (m), 7.08 (d), 6.88-6.49 (m),6.50-6.25 (m), 5.36-4.93 (m), 3.24 (d), 3.18-3.06 (m), 3.04-2.89 (m),2.44 (ddd), 1.83 (d), 1.50-1.19 (m), 1.04 (d).  5 962.2 1H NMR (400 MHz,Methanol-d4) δ 7.76-7.67 (m), 7.60 (dd), 7.17 (q), 7.07 (d), 6.84-6.55(m), 6.49-6.32 (m), 5.34-4.92 (m), 4.78-4.69 (m), 4.09 (q), 3.41-3.28(m), 3.22-2.87 (m), 2.48 (dtt), 2.00 (s), 1.83 (d), 1.53-1.35 (m),1.35-1.19 (m), 1.17-1.00 (m).  6 922.4 1H NMR (400 MHz, Methanol-d4) δ7.73 (t), 7.61 (dd), 7.24-7.02 (m), 6.89-6.50 (m), 6.48-6.31 (m),5.36-4.95 (m), 4.77-4.66 (m), 3.52-3.35 (m), 3.25-3.06 (m), 3.06-2.90(m), 2.46 (dddd), 1.83 (d), 1.50-1.19 (m), 1.14-0.97 (m).  7 940.2 1HNMR (400 MHz, Methanol-d4) δ 7.73 (dd), 7.61 (dd), 7.24-7.11 (m), 7.08(d), 6.87-6.59 (m), 6.40 (ddd), 5.34-4.95 (m), 4.81-4.68 (m), 3.41(ddt), 3.23-2.88 (m), 2.49 (ddd), 1.83 (d), 1.44 (q), 1.35-1.18 (m),1.17-0.95 (m).  8 958.2 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d), 8.64(d), 7.78 (d), 7.72 (d), 7.68-7.62 (m), 7.30-7.06 (m), 6.94-6.54 (m),6.54-6.47 (m), 6.45 (dd), 6.37-6.27 (m), 5.87 (tdd), 5.05 (q), 4.83-4.56(m), 4.44-4.08 (m), 3.96-3.55 (m), 3.56-3.32 (m), 3.27-2.83 (m), 2.45(td), 1.84 (s), 1.54-1.34 (m), 1.35-1.16 (m), 1.03 (q).  9 972.5 — 10956.2 1H NMR (400 MHz, Methanol-d4) δ 8.77 (d), 7.77 (d), 7.75 (d), 7.65(d), 7.62 (d), 7.22 (d), 7.17 (d), 7.11 (d), 6.85 (s), 6.81 (s), 6.77(tt), 6.72 (s), 6.70-6.60 (m), 6.58-6.50 (m), 6.49-6.35 (m), 5.37-5.28(m), 5.08-4.97 (m), 4.77 (s), 4.76 (s), 4.71 (d), 4.66 (s), 3.35 (s),3.19 (d), 3.15 (d), 3.06-2.91 (m), 2.86 (s), 2.53-2.36 (m), 1.84 (s),1.84 (s), 1.61 (s), 1.60 (s), 1.60 (s), 1.45-1.20 (m), 1.13-1.06 (m),1.04-0.96 (m). 11 990.4 1H NMR (400 MHz, Methanol-d4) δ 8.86 (d), 8.72(d), 7.78 (d), 7.72 (d), 7.65 (dd), 7.25-7.10 (m), 6.87-6.64 (m), 6.52(d), 6.43 (dd), 6.38-6.24 (m), 6.19-5.68 (m), 5.05 (q), 4.96-4.53 (m),4.32-4.10 (m), 3.90-3.60 (m), 3.43 (ddq), 3.30-2.80 (m), 2.68-2.29 (m),1.84 (s), 1.52-1.37 (m), 1.37-1.17 (m), 1.17-0.88 (m). 12 934.2 — 13952.2 — 14 948.0 1H NMR (400 MHz, Methanol-d4) δ 8.80-8.67 (m),7.78-7.70 (m), 7.63 (d), 7.60 (d), 7.21-7.15 (m), 7.10 (s), 7.08 (s),6.86 (s), 6.82 (s), 6.78 (tt), 6.72 (s), 6.68 (s), 6.67-6.60 (m), 6.58(s), 6.55 (s), 6.46 (s), 6.44 (s), 6.44-6.34 (m), 5.33-5.22 (m),5.03-4.94 (m), 4.76 (s), 4.76 (s), 4.72 (s), 4.70 (s), 4.66 (s), 3.36(s), 3.34 (s), 3.25-3.18 (m), 3.16 (d), 3.13 (d), 3.06-2.92 (m),2.57-2.35 (m), 1.84 (s), 1.44-1.34 (m), 1.34-1.20 (m), 1.12-1.06 (m),1.06-0.98 (m), 0.73-0.63 (m), 0.57-0.38 (m). 15 966.2 — 16 984.4 1H NMR(400 MHz, Methanol-d4) δ 8.75 (d), 8.66 (d), 7.86-7.57 (m), 7.34-7.05(m), 6.94-6.54 (m), 6.52 (d), 6.45 (dd), 6.38-6.20 (m), 6.18-5.57 (m),5.19-4.97 (m), 4.95-4.46 (m), 4.35-4.09 (m), 3.92-3.39 (m), 3.27-2.76(m), 2.62-2.29 (m), 1.84 (s), 1.51-0.71 (m) 17 976.4 — 18 950.7 1H NMR(Chloroform-d) δ: 7.57 (s), 7.55 (s), 7.49 (s), 7.47 (s), 7.42 (s), 7.21(s), 7.19 (s), 7.01 (s), 6.99 (s), 6.81 (s), 6.69-6.67 (m), 6.67-6.65(m), 6.65-6.62 (m), 6.54 (s), 6.25-6.18 (m), 5.16 (t), 4.94-4.83 (m),4.76-4.68 (m), 4.65 (d), 4.43 (t), 4.35 (t), 3.54-3.48 (m), 3.01-2.90(m), 2.86-2.79 (m), 2.54-2.43 (m), 1.87 (s), 1.45-1.39 (m), 1.33 (s),1.28-1.19 (m), 1.18-1.10 (m) 19 968.8 1H NMR (Chloroform-d) δ: 7.55 (d),7.46 (d), 7.41 (s), 7.18-7.14 (m), 6.99 (d), 6.69-6.62 (m), 6.24-6.22(m), 6.21-6.20 (m), 6.19 (s), 5.15 (t), 4.95-4.88 (m), 4.83 (t),4.76-4.70 (m), 4.68 (d), 4.41 (t), 4.34 (t), 3.50 (s), 3.03-2.95 (m),2.93-2.87 (m), 2.85-2.78 (m), 2.52-2.39 (m), 1.87 (s), 1.48-1.36 (m),1.29-1.18 (m), 1.18-1.10 (m) 20 948.2 1H NMR (400 MHz, Methanol-d4) δ7.73 (m), 7.61 (m), 7.16 (s), 7.07 (m), 6.69 (m), 6.39(m), 5.27 (m,),4.99 (m), 4.73(m), 3.30 (m), 3.13 (m), 2.97 (m), 2.44 (m), 1.83 (d),1.64(d), 1.50-1.19 (m), 1.14-0.8 (m). 21 966.2 1H NMR (400 MHz,Methanol-d4) δ 7.64 (m), 7.52 (m), 7.16 (s), 7.07 (m), 6.97 (m), 6.65(m), 6.29(m), 5.17 (m,), 4.90 (m), 4.75(m), 3.21 (m), 3.05 (m), 2.89(m), 2.38 (m), 1.54 (m), 1.31(m), 1.19 (m), 0.97 (m), 0.71 (m). 221016.3 1H NMR (400 MHz, Methanol-d4) δ 8.94 (d), 7.74-7.64 (m),7.28-7.12 (m), 6.80-6.73 (m), 6.57-6.52 (m), 6.42 (dd), 6.34-6.23 (m),4.84 (d), 4.77 (s), 4.73 (s), 4.67 (d), 4.56 (dd), 3.93 (dd), 3.07 (dd),2.95 (qd), 2.56-2.44 (m), 1.84 (s, 18H), 1.64 (s), 1.41 (d), 1.29 (dd),1.27-1.18 (m), 1.10-0.98 (m), 0.84 (t), 0.80-0.67 (m). 23 1002.2 1H NMR(400 MHz, Methanol-d4) δ 8.84 (d), 8.73 (d), 7.79 (d), 7.72 (d), 7.66(d), 7.26-7.07 (m), 6.86-6.59 (m), 6.59-6.24 (m), 6.18-5.53 (m), 5.05(q), 4.93-4.54 (m), 4.32-3.96 (m), 4.01-3.42 (m), 3.34-2.72 (m),2.68-2.23 (m), 1.84 (s), 1.56-0.72 (m). 24 1006.1 1H NMR (400 MHz,Methanol-d4) δ 8.82 (d), 8.72 (d), 7.84-7.77 (m), 7.77-7.71 (m),7.70-7.65 (m), 7.22-7.19 (m), 7.18-7.12 (m), 6.83 (d), 6.82 (s), 6.77(tt), 6.71-6.67 (m), 6.58-6.48 (m), 6.39-6.31 (m), 6.16-6.11 (m),6.08-5.94 (m), 5.89-5.80 (m), 5.14-5.06 (m), 4.96-4.89 (m), 4.74 (s),4.72 (s), 4.69-4.63 (m), 4.30-4.11 (m), 3.83-3.53 (m), 3.16-3.07 (m),3.02-2.92 (m), 2.51-2.39 (m), 1.85 (s), 1.62 (s), 1.61 (s), 1.60 (s),1.45-1.43 (m), 1.40-1.35 (m), 1.34-1.29 (m), 1.28-1.23 (m), 1.10-0.99(m). 25 1024.2 1H NMR (400 MHz, Methanol-d4) δ 8.89 (d), 8.77 (d), 7.98(s), 7.83-7.77 (m), 7.77-7.71 (m), 7.70-7.64 (m), 7.23-7.11 (m),6.80-6.72 (m), 6.73-6.64 (m), 6.58-6.48 (m), 6.39-6.31 (m), 6.22-6.18(m), 6.14-6.09 (m), 6.07-6.03 (m), 5.97 (s), 5.87-5.78 (m), 5.13-5.04(m), 4.98-4.87 (m), 4.80 (s), 4.78 (s), 4.76-4.65 (m), 4.25-4.08 (m),3.82-3.62 (m), 3.59-3.46 (m), 3.28-3.20 (m), 3.18-3.06 (m), 3.02-2.92(m), 2.86 (s), 2.58-2.40 (m), 1.85 (s), 1.65-1.57 (m), 1.46-1.41 (m),1.42-1.36 (m), 1.34-1.21 (m), 1.07 (s). 26 998.0 1H NMR (400 MHz,Methanol-d4) δ 8.34(m), 7.58-7.29 (m), 7.69-6.70 (m), 7.16 (s), 7.07(m), 6.48-6.25(m), 6.15-6.09(m), 5.92 (m), 5.75-5.28 (m), 4.65(m),4.40-4.30 (m,), 3.79 (m), 3.40-3.00(m), 2.81-2.50 (m), 2.06 (m),1.05-0.80 (m), 0.64 (m), 0.25 (m), 0.03 (m). 27 1016.3 1H NMR (400 MHz,Methanol-d4) δ 8.79(m), 7.88-7.67 (m), 7.07 (m), 6.67 (m), 6.43 (m),6.34(m), 6.22 (m), 5.90-5.60(m), 4.71 (m), 4.06 (m), 3.56(m), 3.26-2.80(m,), 2.40 (m), 1.74 (s), 1.40-0.95(m), 0.55 (m), 0.34 (m). 28 954.1 1HNMR (400 MHz, Methanol-d4) δ 8.90-8.67 (m), 7.80-7.69 (m), 7.68-7.56(m), 7.24-7.14 (m), 7.14-7.04 (m), 6.89-6.70 (m), 6.67 (s), 6.63-6.47(m), 6.46-6.34 (m), 5.09-4.95 (m), 4.70 (s), 4.69 (s), 3.39-3.34 (m),3.21-3.14 (m), 3.06-2.92 (m), 2.53-2.36 (m), 1.87-1.75 (m), 1.44-1.16(m), 1.11-0.96 (m). 29 1034.3 1H NMR (400 MHz, Methanol-d4) δ 8.94 (d),7.82-7.62 (m), 7.27-7.07 (m), 6.84-6.67 (m), 6.61-6.51 (m), 6.42 (dd),6.35-6.23 (m), 4.84 (d), 4.75 (d), 4.67 (d), 4.56 (dd), 3.93 (dd), 3.07(dd), 2.95 (qd), 2.58-2.38 (m), 1.84 (s), 1.64 (d), 1.41 (q), 1.35-1.27(m), 1.27-1.20 (m), 1.12-1.02 (m), 0.84 (t), 0.80-0.69 (m). 30 948.0 1HNMR (400 MHz, Methanol-d4) δ 8.89-8.68 (m), 7.80-7.75 (m), 7.65 (d),7.62 (d), 7.25 (d), 7.20 (d), 7.14-7.07 (m), 6.99 (s), 6.98 (s), 6.85(d), 6.81 (s), 6.78 (tt), 6.72 (s), 6.68 (s), 6.67-6.60 (m), 6.58 (s),6.56-6.49 (m), 6.48-6.38 (m), 5.40-5.26 (m), 5.09-4.97 (m), 4.79 (s),4.77-4.75 (m), 4.71 (s), 4.70 (s), 3.37 (s), 3.22-3.14 (m), 3.08-2.92(m), 2.56-2.38 (m), 1.84 (s), 1.84 (s), 1.84 (s), 1.49-1.18 (m),1.12-0.96 (m). 31 1054.3 1H NMR (400 MHz, Methanol-d4) δ 8.86 (dd),7.82-7.61 (m), 7.31-7.13 (m), 6.84-6.65 (m), 6.48 (d), 6.38-6.24 (m),5.10-4.93 (m), 4.56 (dd), 3.95 (dd), 3.07 (dd), 3.00-2.91 (m), 2.51 (d),1.84 (s), 1.62 (s), 1.36-1.27 (m), 1.25 (dd), 1.20 (s), 0.72 (d). 321048.4 1H NMR (Chloroform-d) δ: 7.60-7.55 (m), 7.55-7.50 (m), 7.28 (s),7.19-7.13 (m), 7.04 (d), 6.69-6.61 (m), 6.21-6.13 (m), 4.84 (q), 4.73(d), 4.48-4.32 (m), 3.92-3.73 (m), 3.02-2.86 (m), 1.84 (s), 1.71-1.64(m), 1.64-1.57 (m), 1.48-1.40 (m), 1.19-1.12 (m), 0.96-0.90 (m),0.89-0.80 (m) 33 1022.1 1H NMR (Chloroform-d) δ: 7.72-7.65 (m),7.59-7.53 (m), 7.24 (s), 7.02-6.95 (m), 6.91 (s), 6.79-6.74 (m), 6.64(s), 6.57-6.50 (m), 6.25 (d), 6.21-6.15 (m), 6.00-5.95 (m), 5.86-5.79(m), 5.36-5.26 (m), 4.95-4.91 (m), 3.86-3.72 (m), 3.70-3.54 (m),3.03-2.88 (m), 2.87-2.76 (m), 2.58-2.40 (m), 1.44-1.33 (m), 1.23-1.15(m), 1.12-1.02 (m) 34 986.2 1H NMR (400 MHz, Methanol-d4) δ 8.85 (t),7.75 (dd), 7.62 (dd), 7.19 (d), 7.08 (d), 6.85-6.72 (m), 6.40 (m),5.07-4.89 (m), 3.34 (s), 3.30-3.12 (m), 3.06-2.90 (m), 2.51 (s), 2.47(d), 1.83 (d), 1.62 (d), 1.36-1.16 (m), 1.22 (s), 0.87-0.66 (m). 351003.2 1H NMR (400 MHz, Methanol-d4) δ 7.85-7.56 (m), 7.32-7.10 (m),6.92-6.56 (m), 6.52 (ddd), 6.40-6.21 (m), 4.76-4.49 (m), 4.01-3.60 (m),3.06 (dd), 3.02-2.79 (m), 2.46 (ddd), 1.84 (s), 1.44-1.19 (m), 1.18-0.92(m). 36 1020.9 1H NMR (400 MHz, Methanol-d4) δ 7.72 (d), 7.66 (d),7.30-7.13 (m), 6.76 (t), 6.46 (d), 6.29 (d), 4.69-4.46 (m), 3.06 (dd),3.02-2.80 (m), 2.49 (s), 1.84 (s), 1.49-1.17 (m), 1.11-0.92 (m). 371036.3 1H NMR (400 MHz, Methanol-d4) δ 8.85 (dd), 7.84-7.62 (m),7.28-7.05 (m), 6.93-6.64 (m), 6.44 (dd), 6.39-6.30 (m), 6.15-5.68 (m),5.05-4.96 (m), 4.94-4.87 (m), 4.26-4.05 (m), 3.86-3.61 (m), 3.09 (dt),3.00-2.91 (m), 2.49 (qd), 1.84 (s), 1.63 (d), 1.36-1.27 (m), 1.27-1.22(m), 1.23-1.16 (m), 0.80-0.66 (m). 38 946.2 — 39 972.2 — 40 900.2 1H NMR(400 MHz, Methanol-d4) δ 7.91-7.85 (m), 7.77-7.72 (m), 7.66-7.58 (m),7.29-7.24 (m), 7.23-7.15 (m), 7.11 (dd), 6.85-6.51 (m), 6.40-6.27 (m),5.36-5.27 (m), 5.06-4.97 (m), 4.81-4.65 (m), 3.33 (s), 3.24-3.16 (m),3.15-3.06 (m), 3.03 (s), 3.02-2.88 (m), 2.80-2.73 (m), 2.73-2.65 (m),2.54-2.37 (m), 1.83 (d), 1.44-1.22 (m), 1.12-0.88 (m). 41 976.2 1H NMR(Chloroform-d) δ: 7.60-7.56 (m), 7.55-7.47 (m), 7.42 (s), 7.41-7.36 (m),7.33-7.29 (m), 7.25-7.24 (m), 7.24-7.22 (m), 7.21-7.17 (m), 7.12-7.06(m), 7.03-6.98 (m), 6.83-6.80 (m), 6.70-6.68 (m), 6.68-6.66 (m),6.66-6.62 (m), 6.56-6.53 (m), 6.52-6.46 (m), 6.24 (dd), 5.31 (t), 5.18(t), 4.95-4.85 (m), 4.83-4.76 (m), 4.75-4.68 (m), 4.65 (d), 4.59 (t),4.51-4.44 (m), 4.43-4.34 (m), 3.16-3.05 (m), 3.03-2.88 (m), 2.87-2.78(m), 2.53-2.41 (m), 1.89-1.85 (m), 1.59-1.48 (m), 1.47-1.33 (m),1.29-1.13 (m) 42 — 1H NMR (400 MHz, Methanol-d4) δ 8.90-8.70(m),7.80-7.66 (m), 7.23-7.05 (m), 6.94-6.70 (m), 6.50 (m), 6.34(m),6.25-5.80 (m), 5.10-4.90(m), 4.18 (m), 3.80-3.60 (m), 3.35-2.90 (m,),2.51 (m), 1.84 (s), 1.28 (m) 43 870.0 1H NMR (400 MHz, Methanol-d4) δ7.74 (dd), 7.65-7.57 (m), 7.24-7.14 (m), 7.09 (d), 7.00-6.56 (m),6.50-6.34 (m), 5.27 (dd), 5.04-4.88 (m), 3.25 (s), 3.21 (s), 3.15 (dd),3.07-2.91 (m), 1.83 (s), 1.39-1.16 (m). 44 878.1 1H NMR (400 MHz,Methanol-d4) δ 7.79-7.70 (m), 7.66-7.57 (m), 7.27 (d), 7.17 (d), 7.11(d), 6.80-6.71 (m), 6.68-6.59 (m), 6.55 (d), 6.46-6.35 (m), 6.25 (s),6.20 (s), 5.31 (dd), 5.01 (t), 4.94-4.86 (m), 3.35-3.32 (m), 3.25 (s),3.22 (s), 3.19-3.12 (m), 3.05-2.90 (m), 1.83 (d), 1.70-1.58 (m),1.58-1.51 (m), 1.36-1.18 (m), 0.97-0.83 (m), 0.72-0.55 (m). 45 771.9 1HNMR (400 MHz, Methanol-d4) δ 9.11 (s), 9.10-8.99 (m), 7.76 (d),7.69-7.58 (m), 7.28-7.14 (m), 7.11 (d), 6.79-6.70 (m), 6.68-6.56 (m),6.56-6.47 (m), 6.42 (t), 5.34-5.25 (m), 5.21 (d), 5.14 (s), 4.98 (q),3.33 (s), 3.27-3.17 (m), 3.06-2.92 (m), 1.83 (d), 1.34-1.22 (m). 46772.0 1H NMR (400 MHz, Methanol-d4) δ 7.76-7.71 (m), 7.61 (dd), 7.23(d), 7.14-7.06 (m), 6.74 (t), 6.67-6.59 (m), 6.51 (d), 6.42 (dd),5.31-5.23 (m), 4.99 (t), 3.95-3.78 (m), 3.25 (s), 3.23 (s), 3.21-3.13(m), 3.07-2.88 (m), 1.83 (s), 1.35-1.17 (m). 47 771.1 1H NMR (400 MHz,Methanol-d4) δ 9.02 (d), 8.93 (d), 8.80 (s), 8.73 (s), 7.78 (d), 7.77(d), 7.64 (d), 7.60 (d), 7.30-7.19 (m), 7.13 (d), 6.80-6.72 (m),6.68-6.60 (m), 6.57-6.54 (m), 6.42 (d), 5.34 (t), 5.01-4.94 (m),4.93-4.86 (m), 3.34 (s), 3.27-3.18 (m), 3.04 (s), 3.03-2.89 (m), 1.83(d), 1.36-1.18 (m). 48 771.0 1H NMR (400 MHz, Methanol-d4) δ 9.01-8.89(m), 7.94 (s), 7.83 (s), 7.77-7.73 (m), 7.70 (s), 7.63 (d), 7.60 (d),5.32-5.26 (m), 5.12 (s), 5.06 (s), 5.03-4.95 (m), 3.28-3.17 (m),3.06-2.92 (m), 1.83 (s), 1.35-1.21 (m). 49 770.1 1H NMR (400 MHz,Methanol-d4) δ 9.04 (d), 8.97 (d), 8.86 (s), 8.73 (t), 7.78 (dd), 7.65(d), 7.61 (d), 7.59-7.56 (m), 7.53-7.48 (m), 7.40-7.35 (m), 7.29 (d),7.20 (d), 7.15 (d), 6.80-6.72 (m), 6.69-6.58 (m), 6.43 (d), 5.39-5.29(m), 5.02-4.90 (m), 4.88 (d), 3.35 (s), 3.29-3.18 (m), 3.07-2.85 (m),1.83 (s), 1.38-1.18 (m). 50 770.0 1H NMR (400 MHz, Methanol-d4) δ 7.74(dd), 7.64-7.50 (m), 7.20 (dd), 7.11 (d), 6.79-6.69 (m), 6.68-6.58 (m),6.53 (d), 6.44-6.33 (m), 6.30 (t), 5.31 (dd), 4.99 (t), 4.80 (s), 4.75(s), 3.28-3.09 (m), 3.02 (s), 3.01-2.91 (m), 1.84 (d), 1.35-1.18 (m). 51938.9 — 52 950.0 — 53 896.1 1H NMR (400 MHz, Chloroform-d) δ 7.57-7.47(m), 7.32 (d), 7.13 (d), 7.02 (d), 6.95 (d), 6.69-6.58 (m), 6.51-6.42(m), 6.20 (t), 6.15 (d), 6.06 (s), 5.54-5.44 (m), 4.99 (q), 4.49 (t),4.45-4.37 (m), 3.40 (s), 3.39 (s), 3.17 (s), 2.99 (s), 2.96-2.75 (m),1.88 (d), 1.83-1.67 (m), 1.45-1.36 (m), 1.29-1.17 (m), 1.09-0.97 (m),0.73-0.58 (m). 54 820.2 1H NMR (400 MHz, Chloroform-d) δ 8.09 (s),7.86-7.76 (m), 7.66-7.49 (m), 7.08 (d), 6.59-6.44 (m), 6.32 (d),6.30-6.18 (m), 4.84-4.69 (m), 4.36-4.08 (m), 3.42 (s), 3.36 (s),3.24-3.12 (m), 3.02 (s), 2.99-2.84 (m), 1.87 (d), 1.43-1.20 (m). 55756.1 — 56 904.1 1H NMR (400 MHz, Chloroform-d) δ 7.67-7.50 (m), 7.38(s), 7.31-7.27 (m), 7.23-7.15 (m), 6.97 (d), 6.92-6.57 (m), 6.55-6.45(m), 6.25 (d), 6.20 (t), 5.60-5.52 (m), 5.06-4.96 (m), 4.93 (s), 3.40(s), 3.39 (s), 3.30 (s), 3.09 (s), 3.04-2.88 (m), 2.85-2.72 (m), 1.87(s), 1.46-1.37 (m), 1.28-1.15 (m). 57 986.0 1H NMR (400 MHz,Methanol-d4) δ 8.88 (d), 8.79 (s), 7.79 (d), 7.72 (d), 7.66 (d), 7.21(dd), 6.90 (d), 6.88 (d), 6.84 (d), 6.81 (d), 6.80-6.73 (m), 6.73-6.64(m), 6.56-6.51 (m), 6.49 (d), 6.47 (d), 6.37-6.29 (m), 6.14-5.74 (m),4.83-4.80 (m), 4.80-4.76 (m), 4.76-4.70 (m), 4.27-4.07 (m), 3.83-3.59(m), 3.28-3.21 (m), 3.12-3.02 (m), 3.01-2.91 (m), 2.90-2.81 (m),2.56-2.41 (m), 1.84 (s), 1.40 (q), 1.35-1.22 (m), 1.16-1.01 (m),1.01-0.92 (m). 58 950.0 1H NMR (400 MHz, Chloroform-d) δ 7.61-7.48 (m),7.37 (s), 7.21-7.08 (m), 7.01-6.46 (m), 6.22 (dd), 5.02 (dd), 4.95 (s),3.40 (s), 3.39 (s), 3.29 (s), 3.09 (s), 3.05-2.88 (m), 2.87-2.69 (m),1.87 (s), 1.44-1.36 (m), 1.29-1.14 (m). 59 910.1 1H NMR (400 MHz,Chloroform-d) δ 7.61-7.48 (m), 7.37 (s), 7.21-7.08 (m), 7.01-6.46 (m),6.22 (dd), 5.02 (dd), 4.95 (s), 3.40 (s), 3.39 (s), 3.29 (s), 3.09 (s),3.05-2.88 (m), 2.87-2.69 (m), 1.87 (s), 1.44-1.36 (m), 1.29-1.14 (m). 60784.2 1H NMR (400 MHz, Chloroform-d) δ 7.71 (s), 7.68 (s), 7.57-7.48(m), 7.40-7.29 (m), 7.20-7.13 (m), 6.98 (d), 6.67-6.59 (m), 6.55-6.42(m), 6.36 (s), 6.31-6.27 (m), 6.22 (d), 5.45 (q), 4.99-4.89 (m), 4.54(d), 3.40 (d), 3.20 (s), 2.94-2.73 (m), 1.87 (s), 1.44-1.37 (m),1.28-1.14 (m). 61 821.1 1H NMR (400 MHz, Chloroform-d) δ 8.22 (d), 8.19(d), 7.85-7.73 (m), 7.59-7.37 (m), 7.37-7.27 (m), 7.25-7.15 (m), 7.13(s), 6.98 (d), 6.62-6.50 (m), 6.49-6.39 (m), 6.33 (d), 6.17-6.04 (m),5.45 (q), 5.08-4.99 (m), 4.95 (q), 3.39 (d), 3.22 (s), 3.08 (s),2.88-2.72 (m), 1.88 (d), 1.45-1.38 (m), 1.26-1.17 (m). 62 820.3 1H NMR(400 MHz, Chloroform-d) δ 9.59 (s), 9.40 (s), 8.30-8.11 (m), 8.07 (s),7.90-7.73 (m), 7.64-7.37 (m), 7.10 (d), 7.02 (d), 6.56 (t), 6.45 (d),6.26 (dd), 5.51-5.37 (m), 5.34-4.90 (m), 3.39 (s), 3.30 (s), 3.28 (s),3.16-2.82 (m), 1.87 (s), 1.32 (d). 63 821.2 1H NMR (400 MHz,Chloroform-d) δ 9.59 (s), 9.40 (s), 8.30-8.11 (m), 8.07 (s), 7.90-7.73(m), 7.64-7.37 (m), 7.10 (d), 7.02 (d), 6.56 (t), 6.45 (d), 6.26 (dd),5.51-5.37 (m), 5.34-4.90 (m), 3.39 (s), 3.30 (s), 3.28 (s), 3.16-2.82(m), 1.87 (s), 1.32 (d). 64 878.3 1H NMR (400 MHz, Chloroform-d) δ7.88-7.73 (m), 7.66 (t), 7.60-7.52 (m), 7.44 (s), 7.40-7.32 (m),7.34-7.18 (m), 7.06 (d), 6.71-6.62 (m), 6.57-6.49 (m), 6.48 (d),6.32-6.27 (m), 6.24-6.18 (m), 5.54 (q), 5.04-4.96 (m), 4.91-4.69 (m),3.40 (s), 3.36 (s), 3.32 (s), 3.17 (s), 3.12-3.01 (m), 2.99-2.88 (m),2.75 (s), 1.85 (s), 1.73 (dt), 1.42-1.35 (m), 1.27-1.16 (m), 1.07 (t).65 838.2 1H NMR (400 MHz, Chloroform-d) δ 7.85 (s), 7.75 (s), 7.62-7.50(m), 7.50-7.44 (m), 7.43-7.36 (m), 7.30 (s), 7.19 (d), 7.02 (d),6.66-6.59 (m), 6.55-6.46 (m), 6.38 (d), 6.21 (td), 5.51 (q), 4.97 (q),4.78 (s), 4.74 (d), 3.41 (s), 3.39 (s), 3.25 (s), 3.13 (s), 3.04-2.86(m), 2.85-2.76 (m), 1.87 (s), 1.45-1.39 (m), 1.29-1.15 (m). 66 770.3 1HNMR (400 MHz, Chloroform-d) δ 8.06 (s), 7.79 (s), 7.63 (d), 7.60-7.49(m), 7.26 (s), 7.13-7.02 (m), 6.61 (t), 6.51 (s), 6.42 (d), 6.27 (dd),5.44-5.22 (m), 4.77 (d), 4.00 (s), 3.41 (s), 3.39 (s), 3.36 (s),3.21-3.13 (m), 3.03-2.97 (m), 2.97-2.87 (m), 1.86 (s), 1.40-1.19 (m). 671008.8 1H NMR (400 MHz, Methanol-d4) δ 8.90 (d), 8.69 (d), 7.90-7.56(m), 7.30-7.05 (m), 6.91-6.62 (m), 6.55 (d), 6.45 (dd), 6.38-6.15 (m),5.48 (s), 5.06-4.91 (m), 4.70-4.48 (m), 4.43-4.05 (m), 3.93 (dq), 3.73(dd), 3.57-3.34 (m), 3.27-3.01 (m), 3.03-2.82 (m), 2.62-2.30 (m), 1.84(s), 1.52-1.35 (m), 1.39-1.17 (m), 1.19-0.81 (m). 68 994.4 1H NMR (400MHz, Methanol-d4) δ 7.81-7.62 (m), 7.28-7.14 (m), 6.81-6.69 (m), 6.55(d, J = 6.9 Hz), 6.46 (d, J = 7.7 Hz), 6.32-6.25 (m), 4.98 (s), 4.88(s), 4.75 (d, J = 16.3 Hz), 4.68-4.62 (m), 4.58 (dd, J = 15.7, 7.5 Hz),4.21 (d, J = 8.0 Hz), 3.93 (dd, J = 16.1, 8.1 Hz), 3.74 (d, J = 7.9 Hz),3.66 (d, J = 5.0 Hz), 3.56 (d, J = 5.0 Hz), 3.22 (s), 3.08 (dd, J =13.4, 7.4 Hz), 3.01-2.88 (m), 2.51 (t, J = 4.5 Hz), 2.48 (s), 1.83 (s),1.41 (q, J = 7.0 Hz), 1.32-1.19 (m). 69 994.2 1H NMR (400 MHz,Methanol-d4) δ 8.85 (dd), 7.97 (s), 7.75-7.53 (m), 7.23 (s), 7.14 (d),6.84-6.56 (m), 6.54-6.38 (m), 5.42-4.96 (m), 4.94-4.50 (m), 4.38 (dt),3.16 (dd), 3.11-2.92 (m), 2.86 (d), 2.67-2.30 (m), 1.84 (d), 1.51-0.93(m).

VIII. Results

Biological Assay Description

The antiviral properties of a compound disclosed herein may bedetermined using Test A described below.

Test A: Antiviral Assay in MT4 Cells

For the antiviral assay, 40 μL of a concentration required to achieve afinal effective 1X test concentration of 3-fold serially dilutedcompound in culture medium with 10% Fetal Bovine Serum (FBS) was addedto each well of a 384-well plate (10 concentrations) in quadruplicate.MT-4 cells were next mixed with HIV-IIIb at a multiplicity of infection(m.o.i) of 0.003 for 1 hour, after which time 35 μL of virus/cellmixture (2000 cells) was immediately added to each well containing 40 μLof diluted compound. The plates were then incubated at 37° C. for 5days.

After 5 days of incubation, 25 μl of 2× concentrated CellTiter-Glo™Reagent (catalog #G7571, Promega Biosciences, Inc., Madison, Wis.) wasadded to each well containing MT-4 cells. Cell lysis was carried out byincubating at room temperature for 10 min and then chemiluminescence wasread. EC50 values were calculated as the compound concentration thatcaused a 50% decrease in luminescence signal, a measure of HIV-1replication. Percent inhibition of virus-induced cell killing calculatedfrom the dose response curve at 200 nM and 10 nM drug concentrations areshown in the table below.

Test B: Cytotoxicity Assay

Compound cytotoxicity and the corresponding CC50 values was determinedusing the same protocol as described in the antiviral assay (Test A)except that uninfected cells were used.

Compounds of the present invention demonstrate antiviral activity (TestA) as depicted in the table below. Shown below are the correspondingvalues for CC50 and percent inhibition of virus-induced cell killing inthe presence of 0.20 μM and 0.01 μM drug concentration.

% inhibition % inhibition Example at 0.20 μM at 0.01 μM CC₅₀ (nM) 1M 9696 >57143 2F 100 100 >57143 3F 100 100 21812 4 92 92 >44108 5 9393 >57143 6 100 100 >57143 7 94 94 >57143 8 94 94 >57143 9 96 96 >5714310 100 100 18453 11 92 92 >57143 12 94 94 >57143 13 100 100 >57143 14100 100 >57143 15 98 98 >57143 16 98 98 >57143 17 98 98 >23951 18 100100 41578 19 97 97 >57143 20 89 89 >57143 21 100 100 >57143 22 9494 >57143 23 100 100 >57143 24 100 100 9074 25 100 100 >57143 26 100100 >57143 27 100 100 >57143 28 99 99 16538 29 100 100 >57143 30 9999 >57143 31 98 97 >57143 32 100 100 >57143 33 97 97 >57143 34 9089 >57143 35 97 97 >57143 36 93 93 >57143 37 92 92 >57143 38 9393 >57143 39 99 99 >57143 40 84 84 >57143 41 100 100 >57143 42 8989 >57143 43 87 87 >57143 44 92 87 >54761 45 97 96 20075 46 10 0 >5461247 0 0 >57143 48 0 0 >57143 49 90 0 >57143 50 36 0 >53589 51 91 67 5119352 93 93 >57143 53 93 93 >57143 54 99 18 29815 55 96 86 22158 56 91 023516 57 91 59 >57143 58 95 95 >57143 59 93 81 >57143 60 100 100 1922561 98 3 28377 62 93 56 30666 63 100 1 21835 64 94 45 >50000 65 10027 >50000 66 97 61 11699 67 0 13 >50000 68 100 100 >50000 69 9292 >50000 70 85 85 >50000

The data above represent an average over time of each assay for eachcompound. For certain compounds, multiple assays have been conductedover the life of the project. Thus, the data reported in the tablesinclude the data reported in the priority document, as well as data fromassays run in the intervening period. In the above table, percentinhibition values have been normalized to 100% where the calculation ofpercent inhibition would have resulted in a value greater than 100

In some embodiments, the compounds demonstrate>10% inhibition at 0.20μM. In one embodiment, the compounds demonstrate>30% inhibition at 0.20μM. In some embodiments, the compounds demonstrate>50% inhibition at0.20 μM. In some embodiments, the compounds demonstrate>70% inhibitionat 0.20 μM. In some embodiments, the compounds demonstrate>75%inhibition at 0.20 μM. In some embodiments, the compoundsdemonstrate>80% inhibition at 0.20 μM. In some embodiments, thecompounds demonstrate>85% inhibition at 0.20 μM. In some embodiments,the compounds demonstrate>90% inhibition at 0.20 μM. In someembodiments, the compounds demonstrate>95% inhibition at 0.20 μM. It isto be understood that the compounds disclosed herein can be groupedaccording to their % inhibition as described above.

In some embodiments, the compounds demonstrate>10% inhibition at 0.20μM. In one embodiment, the compounds demonstrate>30% inhibition at 0.20μM. In some embodiments, the compounds demonstrate>50% inhibition at0.20 μM. In some embodiments, the compounds demonstrate>70% inhibitionat 0.20 μM. In some embodiments, the compounds demonstrate>75%inhibition at 0.20 μM. In some embodiments, the compoundsdemonstrate>80% inhibition at 0.20 μM. In some embodiments, thecompounds demonstrate>85% inhibition at 0.20 μM. In some embodiments,the compounds demonstrate>90% inhibition at 0.20 μM. In someembodiments, the compounds demonstrate>95% inhibition at 0.20 μM. It isto be understood that the compounds disclosed herein can be groupedaccording to their % inhibition as described above.

In some embodiments, a compound is of any formulae provided herein,wherein the compound exhibits from 85%-110% inhibition of virus-inducedcell killing at 0.20 μM. In some embodiments, a compound is of anyformulae provided herein, wherein the compound exhibits from 85%-110%inhibition of virus-induced cell killing at 0.20 μM. In someembodiments, a compound is of any formulae provided herein wherein thecompound exhibits from 50-100, 60-100, 70-100, 80-100, or 90-100%inhibition of virus-induced cell killing at 0.20 μM or at 0.01 μM.

It is understood that % inhibition may be evaluated by techniques knownin the art. In a particular variation, a compound is of any formulaeprovided herein wherein the compound exhibits from 85%-100% inhibitionof virus-induced cell killing at 0.20 μM or at 0.01 μM as measured bythe method provided in the Test A and Test B sections discussed above.

The percent inhibition of virus-induced cell killing at 0.20 μM and 0.01μM was measured by the method provided in the Test A and Test B sectionsdiscussed above.

The specific pharmacological responses observed may vary according toand depending on the particular active compound selected and whetherthere are present pharmaceutical carriers and/or pharmaceutically activecompounds, as well as the type of formulation and mode of administrationemployed, and such expected variations or differences in the results arecontemplated in accordance with practice of the present invention.

The Examples provided herein describe the synthesis of compoundsdisclosed herein as well as intermediates used to prepare the compounds.It is to be understood that individual steps described herein may becombined. It is also to be understood that separate batches of acompound may be combined and then carried forth in the next syntheticstep.

All references, including publications, patents, and patent documentsare incorporated by reference herein, as though individuallyincorporated by reference. The invention has been described withreference to various specific and preferred embodiments and techniques.However, it should be understood that many variations and modificationsmay be made while remaining within the spirit and scope of theinvention.

The use of the terms “a” and “an” and “the” and similar references inthe context of this disclosure (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. All methods described herein can be performed in any suitableorder unless otherwise indicated herein or otherwise clearlycontradicted by context. The use of any and all examples, or exemplarylanguage (e.g., such as, preferred, preferably) provided herein, isintended merely to further illustrate the content of the disclosure anddoes not pose a limitation on the scope of the claims. No language inthe specification should be construed as indicating any non-claimedelement as essential to the practice of the present disclosure.

Alternative embodiments of the claimed disclosure are described herein,including the best mode known to the inventors for practicing theclaimed invention. Of these, variations of the disclosed embodimentswill become apparent to those of ordinary skill in the art upon readingthe foregoing disclosure. The inventors expect skilled artisans toemploy such variations as appropriate (e.g., altering or combiningfeatures or embodiments), and the inventors intend for the invention tobe practiced otherwise than as specifically described herein.Accordingly, this invention includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above describedelements in all possible variations thereof is encompassed by theinvention unless otherwise indicated herein or otherwise clearlycontradicted by context.

The use of individual numerical values is stated as approximations asthough the values were preceded by the word “about” or “approximately.”Similarly, the numerical values in the various ranges specified in thisapplication, unless expressly indicated otherwise, are stated asapproximations as though the minimum and maximum values within thestated ranges were both preceded by the word “about” or “approximately.”In this manner, variations above and below the stated ranges can be usedto achieve substantially the same results as values within the ranges.As used herein, the terms “about” and “approximately” when referring toa numerical value shall have their plain and ordinary meanings to aperson of ordinary skill in the art to which the disclosed subjectmatter is most closely related or the art relevant to the range orelement at issue. The amount of broadening from the strict numericalboundary depends upon many factors. For example, some of the factorswhich may be considered include the criticality of the element and/orthe effect a given amount of variation will have on the performance ofthe claimed subject matter, as well as other considerations known tothose of skill in the art. As used herein, the use of differing amountsof significant digits for different numerical values is not meant tolimit how the use of the words “about” or “approximately” will serve tobroaden a particular numerical value or range. Also, the disclosure ofranges is intended as a continuous range including every value betweenthe minimum and maximum values plus the broadening of the range affordedby the use of the term “about” or “approximately.” Thus, recitation ofranges of values herein are merely intended to serve as a shorthandmethod of referring individually to each separate value falling withinthe range, unless otherwise indicated herein, and each separate value isincorporated into the specification as if it were individually recitedherein. In one aspect, about a value includes and intends that value perse. For example, about x includes and intends x per se.

It is to be understood that any ranges, ratios and ranges of ratios thatcan be formed by, or derived from, any of the data disclosed hereinrepresent further embodiments of the present disclosure and are includedas part of the disclosure as though they were explicitly set forth. Thisincludes ranges that can be formed that do or do not include a finiteupper and/or lower boundary. Accordingly, a person of ordinary skill inthe art most closely related to a particular range, ratio or range ofratios will appreciate that such values are unambiguously derivable fromthe data presented herein.

1. A compound of formula I:

wherein A is 3-6 membered carbocycle; n is 0, 1, or 2; m is 0, 1, or 2;R¹ is

each Z¹ is independently (C1-C6)alkyl, (C3-C7)carbocycle, halogen, or—CN, wherein any (C₁-C₆)alkyl or (C₃-C₇)carbocycle of Z¹ isunsubstituted or substituted with 1, 2, 3, 4 or 5 Z^(1a) groups, whereinthe Z^(1a) groups are the same or different; each Z^(1a) isindependently halogen, (C₃-C₇)carbocycle, —OH, or —CN; R² is hydrogen,halogen, —OH, or —CN; R³ is (C₁-C₆)alkyl or 3-5 membered heterocycle,wherein the (C₁-C₆)alkyl is unsubstituted or substituted with 1, 2, or 3halogen atoms; R⁴ is hydrogen, —S(O)₂—(C₁-C₆)alkyl,—S(O)₂—(C₃-C₆)carbocycle, or 5-6 membered heteroaryl, wherein any—S(O)₂—(C₁-C₆) alkyl, —S(O)₂-(C₃-C₆)carbocycle, or 5-6 memberedheteroaryl of R⁴ is unsubstituted or substituted with 1, 2, or 3 Z²groups, wherein the Z² groups are the same or different; Z² is(C₁-C₆)alkyl or (C₃-C₆)carbocycle, wherein any (C₁-C₆)alkyl or(C₃-C₆)carbocycle is unsubstituted or substituted with 1, 2, or 3 Z²agroups, wherein the Z²a groups are the same or different; Z^(2a) ishydroxyl or halogen; R⁵ is hydrogen or halogen; and R⁶ is (C₁-C₃)alkyl;or a pharmaceutically acceptable salt thereof.
 2. The compound of claim1, or a pharmaceutically acceptable salt thereof, which is a compound offormula Ia:

wherein: n is 0, 1, or 2; m is 0 or 1; each Z¹ is independently(C₁-C₆)alkyl, (C₃-C₇)carbocycle, or halogen, wherein any (C₁-C₆)alkyl or(C₃-C₇)carbocycle of Z¹ is unsubstituted or substituted with 1, 2, 3, 4or 5 Z^(1a) groups, wherein the Z^(1a) groups are the same or different;each Z^(1a) is independently halogen or (C₃-C₇)carbocycle; R² ishydrogen or iodide; R³ is (C₁-C₂)alkyl or 3-5 membered heterocycle,wherein the (C₁-C₂)alkyl is unsubstituted or substituted with 2 or 3halogen atoms; R⁴ is hydrogen, —S(O)₂—(C₁-C₂)alkyl, —S(O)₂-cyclopropyl,or 5-membered heteroaryl, wherein any —S(O)₂—(C₁-C₂)alkyl,—S(O)₂-cyclopropyl, or 5-membered heteroaryl of R⁴ is unsubstituted orsubstituted with 1, 2, or 3 Z² groups, wherein the Z² groups are thesame or different; Z² is (C₁-C₃)alkyl or cyclopropyl, wherein any(C₁-C₃)alkyl or cyclopropyl is unsubstituted or substituted with 1, 2,or 3 Z^(2a) groups, wherein the Z′ groups are the same or different;Z^(2a) is hydroxyl or fluorine; R⁵ is hydrogen, chorine, or fluorine;and R⁶ is (C₁-C₃)alkyl.
 3. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2; m is0 or 1; each Z¹ is independently (C₁-C₆)alkyl, (C₃-C₇)carbocycle, orhalogen, wherein any (C₁-C₆)alkyl or (C₃-C₇)carbocycle of Z¹ isunsubstituted or substituted with 1, 2, 3, 4 or 5 Z^(1a) groups, whereinthe Z^(1a) groups are the same or different; each Z^(1a) isindependently halogen or (C₃-C₇)carbocycle; R² is hydrogen or iodide; R³is (C₁-C₂)alkyl or 3-5 membered heterocycle, wherein the (C₁-C₂)alkyl isunsubstituted or substituted with 2 or 3 fluorine atoms; R⁴ is hydrogen,—S(O)₂—(C₁-C₂)alkyl, —S(O)₂-cyclopropyl, or 5-membered heteroaryl,wherein any —S(O)₂—(C₁-C₂)alkyl, —S(O)₂-cyclopropyl, or 5-memberedheteroaryl of R⁴ is unsubstituted or substituted with 1, 2, or 3 Z²groups, wherein the Z² groups are the same or different; Z² is(C₁-C₃)alkyl or cyclopropyl, wherein any (C₁-C₃)alkyl or cyclopropyl isunsubstituted or substituted with 1, 2, or 3 Z^(2a) groups, wherein theZ^(2a) groups are the same or different; Z^(2a) is hydroxyl or fluorine;R⁵ is hydrogen, chorine, or fluorine; and R⁶ is methyl.
 4. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein: n is0, 1, or 2; m is 0 or 1; each Z¹ is independently (C₁-C₆)alkyl,(C₃-C₇)carbocycle, or halogen, wherein any (C₁-C₆)alkyl or(C₃-C₇)carbocycle of Z¹ is unsubstituted or substituted with 1, 2, 3, 4or 5 Z^(1a) groups, wherein the Z^(1a) groups are the same or different;each Z^(1a) is independently halogen or (C₃-C₇)carbocycle; R² ishydrogen; R³ is (C₁-C₂)alkyl or 4-membered heterocycle, wherein the(C₁-C₂)alkyl is unsubstituted or substituted with 2 or 3 fluorine atoms;R⁴ is —S(O)₂—(C₁-C₂)alkyl, —S(O)₂-cyclopropyl, or 5-membered heteroaryl,wherein any —S(O)₂—(C₁-C₂)alkyl, —S(O)₂-cyclopropyl, or 5-memberedheteroaryl of R⁴ is unsubstituted or substituted with 1, 2, or 3 Z²groups, wherein the Z² groups are the same or different; Z² is(C₁-C₃)alkyl or cyclopropyl, wherein any (C₁-C₃)alkyl or cyclopropyl isunsubstituted or substituted with 1, 2, or 3 Z^(2a) groups, wherein theZ^(2a) groups are the same or different; Z^(2a) is hydroxyl or fluorine;R⁵ is hydrogen, chorine, or fluorine; and R⁶ is methyl.
 5. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein nis
 1. 6. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein m is
 0. 7. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is


8. (canceled)
 9. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is


10. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹ is


11. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹ is


12. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹ is


13. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹ is

14.-15. (canceled)
 16. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein Z¹ is (C₁-C₆)alkyl substituted with 2or 3 halogen atoms, a cyclopropyl group, or halogen. 17.-18. (canceled)19. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R² is hydrogen or iodide. 20.-21. (canceled)
 22. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R³ is (C₁-C₃)alkyl or a 4-membered heterocycle, wherein the(C₁-C₃)alkyl is unsubstituted or substituted with 1, 2, or 3 halogenatoms.
 23. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R³ is methyl, —CH₂CHF₂, —CH₂CF₃, or


24. (canceled)
 25. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is hydrogen, —S(O)₂—(C₁₋₂)alkyl,—S(O)₂-cyclopropyl, or an oxadiazole, wherein any —S(O)₂—(C₁₋₂)alkyl,—S(O)₂-cyclopropyl, or oxadiazole of R⁴ is unsubstituted or substitutedwith 1, 2, or 3 Z² groups, wherein the Z² groups are the same ordifferent.
 26. (canceled)
 27. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁴ is

28.-29. (canceled)
 30. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is hydrogen, chloride, or fluoride.31.-33. (canceled)
 34. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, which is

35.-41. (canceled)
 42. A pharmaceutical composition comprising acompound of claim 1, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier.
 43. (canceled)
 44. A method fortreating a HIV infection in a patient in need thereof comprisingadministering a therapeutically effective amount of a compound of claim1, or a pharmaceutically acceptable salt thereof, to the patient.
 45. Amethod for treating an HIV infection in a patient in need thereofcomprising administering to the patient a therapeutically effectiveamount of a compound of claim 1, or a pharmaceutically acceptable saltthereof, in combination with a therapeutically effective amount of anadditional therapeutic agent, wherein the additional therapeutic agentis a HIV protease inhibitor, a HIV non-nucleoside or non-nucleotideinhibitor of reverse transcriptase, a HIV nucleoside or nucleotideinhibitor of reverse transcriptase, a HIV integrase inhibitor, a HIVnon-catalytic site integrase inhibitor, an HIV entry inhibitor, an HIVmaturation inhibitor, a latency reversing agent, a compound that targetsthe HIV capsid, an immune-based therapy, a phosphatidylinositol 3-kinase(PI3K) inhibitor, a HIV antibody, a bispecific antibody, anantibody-like therapeutic protein, a HIV p17 matrix protein inhibitor, aIL-13 antagonist, a peptidyl-prolyl cis-trans isomerase A modulator, aprotein disulfide isomerase inhibitor, a complement C5a receptorantagonist, a DNA methyltransferase inhibitor, a HIV vif gene modulator,a Vif dimerization antagonist, a HIV-1 viral infectivity factorinhibitor, a TAT protein inhibitor, a HIV-1 Nef modulator, a Hcktyrosine kinase modulator, a mixed lineage kinase-3 (MLK-3) inhibitor, aHIV-1 splicing inhibitor, a Rev protein inhibitor, an integrinantagonist, a nucleoprotein inhibitor, a splicing factor modulator, aCOMM domain containing protein 1 modulator, a HIV ribonuclease Hinhibitor, a retrocyclin modulator, a CDK-9 inhibitor, a dendriticICAM-3 grabbing nonintegrin 1 inhibitor, a HIV GAG protein inhibitor, aHIV POL protein inhibitor, a Complement Factor H modulator, a ubiquitinligase inhibitor, a deoxycytidine kinase inhibitor, a cyclin dependentkinase inhibitor, a proprotein convertase PC9 stimulator, a ATPdependent RNA helicase DDX3X inhibitor, a reverse transcriptase primingcomplex inhibitor, a G6PD and NADH-oxidase inhibitor, a pharmacokineticenhancer, a HIV gene therapy, or a HIV vaccine. 46.-49. (canceled)